by Talib - PowerPoint Presentation

Slide1

by

Talib F. Abbas

Human Physiology

GIT PhysiologySlide2

Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice. About 500 mL is secreted per day. Some of the components of the bile are reabsorbed reabsorbed in the intestine and then excreted again by the liver

(enterohepatic circulation). The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile.

BilesSlide3
Slide4

The bile acids secreted into the bile are conjugated to glycine or taurine, a derivative of

cysteine. The bile acids are synthesized from cholesterol. The four major bile acids found in humans are list above. In common with vitamin D, cholesterol, a variety of steroid hormones, and the digitalis glycosides, the bile acids contain the steroid nucleus . The two principal (primary) bile acids formed in the liver are cholic acid and chenodeoxycholic acid. In the colon, bacteria convert cholic acid to deoxycholic acid and chenodeoxycholic

acid to

lithocholic

acid. In addition, small quantities of

ursodeoxycholic

acid are formed from

chenodeoxycholic acid. Ursodeoxycholic acid is a tautomer of chenodeoxycholic acid at the 7-position. Because they are formed by bacterial action, deoxycholic, lithocholic, and ursodeoxycholic acids are called secondary bile acids.

The Bile Acids Slide5

Compostion of Biles )Maradona )Slide6

The bile salts have a number of important actions: they reduce surface tension and, in conjunction with phospholipids and monoglycerides, are responsible for the emulsification of fat preparatory to its digestion and absorption in the small intestine. They are

amphipathic, that is, they have both hydrophilic and hydrophobic domains; one surface of the molecule is hydrophilic because the polar peptide bond and the carboxyl and hydroxyl groups are on that surface, whereas the other surface is hydrophobic. Therefore, the bile salts tend to form cylindrical disks called micelles.Mardona composition of human bile duct bile. Slide7

. Their hydrophilic portions face out and their hydrophobic portions face in. Above a certain concentration, called the critical micelle concentration, all

bile salts added to a solution form micelles. Lipids collect in the micelles, with cholesterol in the hydrophobic center and amphipathic phospholipids and monoglycerides lined up with their hydrophilic heads on the outside and their hydrophobic tails in the center. The micelles play an important role in keeping lipids in solution and transporting them to the brush border of the intestinal epithelial cells, where they are absorbed.

Biles Slide8

Biles (solaf method of absorption)

Ninety to 95% of the bile salts are absorbed from the small intestine. Once they are deconjugated, they can be absorbed by nonionic diffusion, but most are absorbed in their conjugated forms from the terminal ileum by an extremely efficient Na+–bile salt cotransport system powered by basolateral Na+–K+ ATPase. The remaining 5–10% of the bile salts enter the colon and are converted to the salts of deoxycholic acid and

lithocholic

acid.

Lithocholate

is relatively insoluble and is mostly excreted in the stools; only 1% is absorbed. However,

deoxycholate

is absorbed began from sphincter of Oddi. Slide9

Biles ( Graphic of AlDama mobile action) Slide10

The absorbed bile salts are transported back to the liver in the portal vein and reexcreted in the bile (enterohepatic

circulation) Those lost in the stool are replaced by synthesis in the liver; the normal rate of bile salt synthesis is 0.2 to 0.4 g/d. The total bile salt pool of approximately 3.5 g recycles repeatedly via the enterohepatic circulation; it has been calculated that the entire pool recycles twice per meal and six to eight times per day. When bile is excluded from the intestine, up to 50% of ingested fat appears in the feces. A severe malabsorption of fat-soluble vitamins also results. When bile salt reabsorption is prevented by resection of the terminal ileum or by disease in this portion of the small intestine, the amount of fat in the stools is also increased because when the enterohepatic

circulation is interrupted, the liver cannot increase the rate of bile salt production to a sufficient degree to compensate for the loss.

Biles Slide11

The various functions of the gastrointestinal tract, including secretion, digestion, and absorption and motility must be regulated in an integrated way to ensure efficient assimilation of nutrients after a meal. There are three main modalities for gastrointestinal regulation that operate in a complementary fashion to ensure that function is appropriate. 1- Endocrine

2-Paracrine 3-extrinsic innervation (enteric nervous system) ( Lancaster ) secreto-motor neurons Gastrointestinal RegulationSlide12

Gastrointestinal RegulationFirst,

endocrine regulation is mediated by the release of hormones by triggers associated with the meal. These hormones travel through the bloodstream to change the activity of a distant segment of the gastrointestinal tract, an organ draining into it (eg, the pancreas), or both.Second, some similar mediators are not sufficiently stable to persist in the bloodstream, but instead alter the function of cells in the local area where they are released, in a paracrine fashion.

Finally

, the intestinal system is endowed with extensive neural connections. These include connections to the central nervous system

(extrinsic

innervation

), but also the activity of a largely autonomous enteric nervous system that comprises both sensory and secreto-motor neurons.Slide13

The enteric nervous system integrates central input to the gut, but can also regulate gut function independently in response to changes in the luminal environment. In some cases, the same substance can mediate regulation by endocrine, paracrine, and

neurocrine pathways (eg, cholecystokinin,).Enteric nervous system ( 2 hours)Slide14

Peristalsis is a reflex response that is initiated when the gut wall is stretched by the contents of the lumen, and it occurs in all parts of the gastrointestinal tract from the esophagus to the rectum. The stretch initiates a circular contraction (felka)behind

the stimulus and an area of relaxation in front of it. The wave of contraction then moves in an oral-to-caudal direction, propelling the contents of the lumen forward at rates that vary from 2 to 25 cm/s. Peristaltic activity can be increased or decreased by the autonomic input to the gut, but its occurrence is independent of the extrinsic innervation. Indeed, progression of the contents is not blocked by removal and resuture of a segment of intestine in its original position and is blocked only if the segment is reversed before it is sewn back into place.

Peristalisis

(Paris-taltic activity)Slide15

Peristalsis is an excellent example of the integrated activity of the enteric nervous system. It appears that local stretch releases serotonin, which activates sensory neurons that activate the myenteric plexus. Cholinergic neurons passing in a retrograde direction in this plexus activate neurons that release substance P and acetylcholine, causing smooth muscle contraction. At the same time, cholinergic neurons passing in an

anterograde the setting of segmentation. This mixing pattern persists for as long as nutrients remain in the lumen to be absorbed. It presumably reflects programmed activity of the bowel dictated by the enteric nervous system, and can occur independent of central input, although the latter can modulate it.Peristalisis (Paris-taltic activity)Slide16

The portion of the pancreas that secretes pancreatic juice is a compound alveolar gland resembling the salivary glands. Granules containing the digestive enzymes (zymogen granules) are formed in the cell and discharged by

exocytosis. from the apexes of the cells into the lumens of the pancreatic ducts. The small duct radicles coalesce into a single duct (pancreatic duct of Wirsung), which usually joins the common bile duct to form the ampulla of Vater. The ampulla opens through the duodenal papilla, and its orifice is encircled by the sphincter of Oddi

. Some individuals have an accessory pancreatic duct (duct of

Santorini

) that enters the duodenum more proximally.

Pancreas

ducts ( Wirsung & santor)Slide17

PancreasSlide18

The pancreatic juice is alkaline and has a high HCO3–content (approximately 113 mEq/L vs. 24 mEq/L in plasma). About 1500 mL

of pancreatic juice is secreted per day. Bile and intestinal juices are also neutral or alkaline, and these three secretions neutralize the gastric acid, raising the pH of the duodenal contents to 6.0 to 7.0. By the time the chyme reaches the jejunum, its pH is nearly neutral, but the intestinal contents are rarely alkaline. The potential danger of the release into the pancreas of a small amount of trypsin is apparent; the resulting chain reaction would produce active enzymes that could digest the pancreas. It is therefore not surprising that the pancreas normally contains a trypsin inhibitor.

Pancreas

and Trypsin Slide19

Another enzyme activated by trypsin is phospholipase A2. This enzyme splits a fatty acid off phosphatidylcholine (PC), forming

lyso-PC. Lyso-PC damages cell membranes. It has been hypothesized that in acute pancreatitis, a severe and sometimes fatal disease, phospholipase A2 is activated in the pancreatic ducts, with the formation of lyso-PC from the PC that is a normal constituent of bile. This causes disruption of pancreatic tissue and necrosis of surrounding fat. Small amounts of pancreatic digestive enzymes normally leak into the circulation, but in acute pancreatitis, the circulating levels of the digestive enzymes rise markedly. Measurement of the plasma amylase or lipase concentration is therefore of value in diagnosing the disease.

Pancreas

and Phosp

holipase A2Slide20

Pancreas and Hormons The presence in the pancreatic islets of hormones that affect the secretion of other islet hormones suggests that the islets function as

secretory units in the regulation of nutrient homeostasis. Somatostatin inhibits the secretion of insulin, glucagon, and pancreatic polypeptide; insulin inhibits the secretion of glucagon; and glucagon stimulates the secretion of insulin and somatostatin. As noted above, A and D cells and pancreatic polypeptide-secreting cells are generally located around the periphery of the islets, with the B cells in the center. There are clearly two types of islets, glucagon-rich islets and pancreatic polypeptide-rich islets, but the functional significance of this separation is not known. The islet cell hormones released into the ECF probably diffuse to other islet cells and influence their function (paracrine

communication;. It has been demonstrated that gap junctions are present between A, B, and D cells and that these permit the passage of ions and other small molecules from one cell to another, which could coordinate their

secretory

functions.Slide21

Human pancreatic polypeptide is a linear polypeptide that contains 36 amino acid residues and is produced by F cells in the islets. It is closely related to two other 36-amino acid polypeptides, polypeptide YY, a gastrointestinal peptide, and neuropeptide

Y, which is found in the brain and the autonomic nervous system. All end in tyrosine and are amidated at their carboxyl terminal. At least in part, pancreatic polypeptide secretion is under cholinergic control; plasma levels fall after administration of atropine. Its secretion is increased by a meal containing protein and by fasting, exercise, and acute hypoglycemia. Secretion is decreased by somatostatin and intravenous glucose. Infusions of leucine, arginine, and alanine

do not affect it, so the stimulatory effect of a protein meal may be mediated indirectly. Pancreatic polypeptide slows the absorption of food in humans, and it may smooth out the peaks and valleys of absorption. However, its exact physiologic function is still uncertain.

Pancreas and F cell

(Hamilton)Slide22

Secretion of pancreatic juice is primarily under hormonal controlSecretin acts on the pancreatic ducts to cause copious secretion of a very alkaline pancreatic juice that is rich in HCO3– and poor in enzymes. The effect on duct cells is due to an increase in intracellular

cAMP. Secretin also stimulates bile secretion.Regulation of the secretion of pancreatic juiceSlide23

Secretion of pancreatic juice is primarily under hormonal controlCCK acts on the acinar

cells to cause the release of zymogen granules and production of pancreatic juice rich in enzymes but low in volume. Its effect is mediated by phospholipase C. The response to intravenous secretin.Regulation of the secretion of pancreatic juiceSlide24

Note that as the volume of pancreatic secretion increases, its Cl–concentration falls and its HCO3–concentration increases. Although HCO3–is secreted in the small ducts, it is reabsorbed in the large ducts in exchange for Cl–. The magnitude of the exchange is inversely proportionate to the rate of flow.

Like CCK, acetylcholine acts on acinar cells via phospholipase C to cause discharge of zymogen granules, and stimulation of the vagi causes secretion of a small amount of pancreatic juice rich in enzymes. There is evidence for vagally mediated conditioned reflex secretion of pancreatic juice in response to the sight or smell of food.

Regulation of the secretion of pancreatic juiceSlide25

An important function of the liver is to serve as a filter between the blood coming from the gastrointestinal tract and the blood in the rest of the body. Blood from the intestines and other viscera reach the liver via the portal vein. This blood percolates in sinusoids between plates of hepatic cells and eventually drains into the hepatic veins, which enter the inferior vena cava. During its passage through the hepatic plates, it is extensively modified chemically. Bile is formed on the other side at each plate. The bile passes to the intestine via the hepatic duct. In each hepatic lobule, the plates of hepatic cells are usually only one cell thick

LiverSlide26

Large gaps occur between the endothelial cells, and plasma is in intimate contact with the cells . Hepatic artery blood also enters the sinusoids. The central veins coalesce to form the hepatic veins, which drain into the inferior vena cava. The average transit time for blood across the liver lobule from the portal venule

to the central hepatic vein is about 8.4 s. Additional details of the features of the hepatic micro- and macrocirculation, which are critical to organ function, are provided below. Numerous macrophages (Kupffer cells) are anchored to the endothelium of the sinusoids and project into the lumen. Liver Slide27

Liver Central viens CVSlide28

Each liver cell is also apposed to several bile canaliculi . The canaliculi drain into intralobular

bile ducts, and these coalesce via interlobular bile ducts to form the right and left hepatic ducts. These ducts join outside the liver to form the common hepatic duct. The cystic duct drains the gallbladder. The hepatic duct unites with the cystic duct to form the common bile duct. The common bile duct enters the duodenum at the duodenal papilla. Its orifice is surrounded by the sphincter of Oddi, and it usually unites with the main pancreatic duct just before entering the duodenum. The sphincter is usually closed, but when the gastric contents enter the duodenum, cholecystokinin (CCK) is released and the gastrointestinal hormone relaxes the sphincter and makes the gallbladder contract.

Liver & sphincter of OddiSlide29

The walls of the extrahepatic biliary ducts and the gallbladder contain fibrous tissue and smooth muscle. They are lined by a layer of columnar cells with scattered mucous glands. In the gallbladder, the surface is extensively folded; this increases its surface area and gives the interior of the gallbladder a honeycombed appearance. The cystic duct is also folded to form the so-called spiral valves. This arrangement is believed to increase the turbulence of bile as it flows out of the gallbladder, thereby reducing the risk that it will precipitate and form gallstones.

Liver & Cystic ductSlide30

It is beyond the scope of this volume to touch upon all of the metabolic functions of the liver. Instead, we will describe here those aspects most closely aligned to gastrointestinal physiology. First, the liver plays key roles in carbohydrate metabolism, including glycogen storage, conversion of galactose

and fructose to glucose, and gluconeogenesis. The substrates for these reactions derive from the products of carbohydrate digestion and absorption that are transported from the intestine to the liver in the portal blood. The liver also plays a major role in maintaining the stability of blood glucose levels in the postprandial period, removing excess glucose from the blood and returning it as needed—the so-called glucose buffer function of the liver. In liver failure, hypoglycemia is commonly seen.

Functions of Liver

(sopic ) Slide31

Similarly, the liver contributes to fat metabolism. It supports a high rate of fatty acid oxidation for energy supply to the liver itself and other organs. Amino acids and two carbon fragments derived from carbohydrates are also converted in the liver to fats for storage. The liver also synthesizes most of the lipoproteins required by the body and preserves cholesterol homeostasis by synthesizing this molecule and also converting excess cholesterol to bile acids. The liver also detoxifies the blood of substances originating from the gut or elsewhere in the body . Part of this function is physical in nature—bacteria and other

particulates are trapped in and broken down by the strategicallylocated Kupffer cells.Liver and FatSlide32

The remaining reactions are biochemical, and mediated in their first stages by the large number of cytochrome P450 enzymes expressed in hepatocytes. These convert

xenobiotics and other toxins to inactive, less lipophilic metabolites. Detoxification reactions are divided into phase I (oxidation, hydroxylation, and other reactions mediated by cytochrome P450s) and phase II (esterification). Ultimately, metabolites are secreted into the bile for elimination via the gastrointestinal tract. In this regard, in addition to disposing of drugs, the liver is responsible for metabolism of essentially all steroid hormones. Liver disease can therefore result in the apparent overactivity of the relevant hormone systems.

Detoxifixation of xinobiotics Slide33

Thank you