DIGESTIVE SYSEM

OVERVIEW:

The digestive system includes the gastrointestinal (GI) tract (or alimentary canal), consisting of the mouth, pharynx, esophagus, stomach, small intestine, and large intestine; and the accessory organs and tissues, consisting of the salivary glands, liver, gallbladder, and exocrine pancreas. The accessory organs are not part of the tract but secrete substances into it via connecting ducts. The overall function of the digestive system is to process ingested foods into molecular forms that are then transferred, along with small molecules, ions, and water, to the body’s internal environment, where the circulatory system can distribute them to cells. The digestive system is under the local neural control of the enteric nervous system and also of the central nervous system. The adult gastrointestinal tract is a tube approximately 9 m (30 feet) in length, running through the body from mouth to anus. The lumen of the tract is continuous with the external environment, which means that its contents are technically outside the body. This fact is relevant to understanding some of the tract’s properties. For example, the large intestine is colonized by billions of bacteria, most of which are harmless and even beneficial in this location. However, if the same bacteria enter the internal environment, as may happen, for example, if a portion of the large intestine is perforated, they may cause a severe infection.

Most food enters the gastrointestinal tract as large particles containing macromolecules, such as proteins and polysaccharides, which are unable to cross the intestinal epithelium. Before ingested food can be absorbed, therefore, it must be dissolved and broken down into small molecules. (Small nutrients such as vitamins and minerals do not need to be broken down and can cross the epithelium intact.) This dissolving and breaking-down process is called digestion and is accomplished by the action of hydrochloric acid in the stomach, bile from the liver, and a variety of digestive enzymes released by the system’s exocrine glands. Each of these substances is released into the lumen of the GI tract through the process of secretion. In addition, some digestive enzymes are located on the apical membranes of the intestinal epithelium. The molecules produced by digestion, along with water and small nutrients that do not require digestion, then move from the lumen of the gastrointestinal tract across a layer of epithelial cells and enter the blood or lymph. This process is called absorption.

While digestion, secretion, and absorption are taking place, contractions of smooth muscles in the gastrointestinal tract wall occur, where they serve two functions: They mix the luminal contents with the various secretions, and they move the contents through the tract from mouth to anus. These contractions are referred to as the motility of the gastrointestinal tract. In some cases, muscular movements travel in a wavelike fashion in one direction along the length of a part of the tract, a process called peristalsis. The functions of the digestive system can be described in terms of these four major processes—digestion, secretion, absorption, and motility—and the mechanisms controlling them. Within fairly wide limits, the digestive system will absorb as much of any particular substance that is ingested, with a few important exceptions (to be described later). Therefore, the digestive system does not regulate the total amount of nutrients absorbed or their concentrations in the internal environment. The plasma concentration and distribution of the absorbed nutrients throughout the body are primarily controlled by hormones from a number of endocrine glands and by the kidneys. Small amounts of certain metabolic end products are excreted via the gastrointestinal tract, primarily by way of the bile. This represents a relatively minor function of the GI tract in healthy individuals—elimination. In fact, the lungs and kidneys are usually responsible for the elimination of most of the body’s waste products, such as CO2. The material known as feces leaves the system via the anus at the end of the gastrointestinal tract. Feces consist almost entirely of bacteria and ingested material that was neither digested nor absorbed, and therefore, was never actually absorbed into the internal environment.

Four major processes the gastrointestinal tract carries out: digestion, secretion, absorption, and motility. Outward-pointing (black) arrows indicate absorption of the products of digestion, water, minerals, and vitamins into the blood. Inward-pointing (red) arrows represent the secretion of ions, enzymes, and bile salts into the GI tract. The length and density of the arrows indicate the relative importance of each segment of the tract; the small intestine is where most digestion, absorption, and secretion occurs. The feces represent a fifth function of the GI tract: elimination. The wavy configuration of the small intestine represents muscular contractions (motility) throughout the tract.

Functions of the Organs of the Digestive System

Defecation

After electrolytes and water have been absorbed the waste material that is left passes to the rectum, leading to an increase in rectal pressure, relaxation of the internal anal sphincter, and the urge to defecate. If the urge to defecate is denied, feces are prevented from entering the anal canal by the external anal sphincter. In this case, the feces remain in the rectum, and may even back up into the sigmoid colon. The defecation reflex normally occurs when the rectal pressure rises to a particular level that is determined, to a large degree, by habit. At this point the external anal sphincter relaxes to admit feces into the anal canal. During the act of defecation, the longitudinal rectal muscles contract to increase rectal pressure, and the internal and external anal sphincter muscles relax. Excretion is aided by contractions of abdominal and pelvic skeletal muscles, which raise the intra-abdominal pressure. The raised pressure helps push the feces from the rectum, through the anal canal, and out of the anus.

Major digestive enzymes:

Enzymes of pancreas:

Effects of Gastric Hormones:

Phases of Gastrointestinal Control:

The neural and hormonal control of the digestive system is, in large part, divisible into three phases—cephalic, gastric, and intestinal—according towhere the stimulus is perceived.

The cephalic (from a Greek word for “head”) phase is initiated when sensory receptors in the head are stimulated by sight, smell, taste, and chewing. Various emotional states can also initiate this phase. The efferent pathways for these reflexes are primarily mediated by parasympathetic fibers carried in the vagus nerves. These fibers activate neurons in the gastrointestinal nerve plexuses, which in turn affect secretory and contractile activity.

Four stimuli in the stomach initiate the reflexes that constitute the gastric phase of regulation: distension, acidity, amino acids, and peptides formed during the partial digestion of ingested protein. The responses to these stimuli are mediated by short and long neural reflexes and by release of the hormone gastrin.

Finally, the intestinal phase is initiated by stimuli in the small intestine including distension, acidity, osmolarity, and various digestive products. The intestinal phase is mediated by both short and long neural reflexes and by the hormones secretin, CCK, and GIP, all of which are secreted by enteroendocrine cells of the small intestine. Each of these phases is named for the site at which the various stimuli initiate the reflex and not for the sites of effector activity. Each phase is characterized by efferent output to virtually all organs in the gastrointestinal tract. Also, these phases do not occur in temporal sequence except at the very beginning of a meal. Rather, during ingestion and the much longer absorptive period, reflexes characteristic of all three phases may be occurring simultaneously.

Digestion and Absorption of carbohydrates

The average daily intake of carbohydrates is about 250 to 300 g per day in a typical American diet. This represents about half the average daily intake of calories. About two-thirds of this carbohydrate is the plant polysaccharide starch, and most of the remainder consists of the disaccharides sucrose (table sugar) and lactose (milk sugar). Only small amounts of monosaccharides are normally present in the diet. Cellulose and certain other complex polysaccharides found in vegetable matter—referred to as dietary fiber (or simply fiber)—are not broken down by the enzymes in the small intestine and pass on to the large intestine, where they are partially metabolized by bacteria. The digestion of starch by salivary amylase begins in the mouth but accounts for only a small fraction of total starch digestion. It continues very briefly in the upper part of the stomach before gastric acid inactivates the amylase. Most (~95% or more) starch digestion is completed in the small intestine by pancreatic amylase.

The products of both salivary and pancreatic amylase are the disaccharide maltose and a mixture of short, branched chains of glucose molecules. These products, along with ingested sucrose and lactose, are broken down into monosaccharides—glucose, galactose, and fructose—by enzymes located on the apical membranes of the small-intestine epithelial cells (brush border). These monosaccharides are then transported across the intestinal epithelium into the blood. Fructose enters the epithelial cells by facilitated diffusion via a glucose transporter (GLUT), whereas glucose and galactose undergo secondary active transport coupled to Na1 via the sodium–glucose cotransporter (SGLT). These monosaccharides then leave the epithelial cells and enter the interstitial fluid by way of facilitated diffusion via various GLUT proteins in the basolateral membranes of the epithelial cells. From there, the monosaccharides diffuse into the blood through capillary pores. Most ingested carbohydrates are digested and absorbed within the first 20% of the small intestine.

Digestion and Absorption of proteins

A healthy adult requires a minimum of about 40 to 50 g of protein per day to supply essential amino acids and replace the nitrogen contained in amino acids that are metabolized to urea. A typical American diet contains about 60 to 90 g of protein per day. This represents about one-sixth of the average daily caloric intake. In addition, a large amount of protein, in the form of enzymes and mucus, is secreted into the GI tract or enters it via the death and disintegration of epithelial cells. Regardless of the source, most of the protein in the lumen is broken down into dipeptides, tripeptides, and amino acids, all of which are absorbed by the small intestine.

Proteins are first partially broken down to peptide fragments in the stomach by the enzyme pepsin that is produced from an inactive precursor pepsinogen. Further breakdown is completed in the small intestine by the enzymes trypsin and chymotrypsin, the major proteases secreted by the pancreas. These peptide fragments can be absorbed if they are small enough or are further digested to free amino acids by carboxypeptidases (additional proteases secreted by the pancreas) and aminopeptidases, located on the apical membranes of the small-intestine epithelial cells. These last two enzymes split off amino acids from the carboxyl and amino ends of peptide fragments, respectively. At least 20 different peptidases are located on the apical membrane of the epithelial cells, with various specificities for the peptide bonds they attack. Most of the products of protein digestion are absorbed as short chains of two or three amino acids by secondary active transport coupled to the H⁺ gradient. The absorption of small peptides contrasts with carbohydrate absorption, in which molecules larger than monosaccharides are not absorbed. Free amino acids, by contrast, enter the epithelial cells by secondary active transport coupled to Na⁺. There are many different amino acid transporters that are specific for the different amino acids, but only one transporter for simplicity. Within the cytosol of the epithelial cell, the dipeptides and tripeptides are hydrolyzed to amino acids; these, along with free amino acids that entered the cells, then leave the cell and enter the interstitial fluid through facilitated-diffusion transporters in the basolateral membranes. As with carbohydrates, protein digestion and absorption are largely completed in the upper portion of the small intestine.

Very small amounts of intact proteins are able to cross the intestinal epithelium and gain access to the interstitial fluid. They do so by a combination of endocytosis and exocytosis. The absorptive capacity for intact proteins is much greater in infants than in adults, and antibodies (proteins involved in the immunologic defense system of the body) secreted into the mother’s milk can be absorbed intact by the infant, providing some immunity until the infant’s immune system matures.

Digestion and Absorption of fats

Emulsification of fat by bile salts and phospholipids. Note that the nonpolar sides (green) of bile salts and phospholipids are oriented toward fat, whereas the polar sides (red) of these compounds are oriented outward.

Digestion Triglyceride digestion occurs to a limited extent in the mouth and stomach, but it predominantly occurs in the small intestine. The major digestive enzyme in this process is pancreatic lipase, which catalyzes the splitting of bonds linking fatty acids to the first and third carbon atoms of glycerol, producing two free fatty acids and a monoglyceride as products:

Emulsification The lipids in the ingested foods are insoluble in water and aggregate into large lipid droplets in the upper portion of the stomach. This is like a mixture of oil and vinegar after shaking. Because pancreatic lipase is a water soluble enzyme, its digestive action in the small intestine can take place only at the surface of a lipid droplet. Therefore, if most of the ingested fat remained in large lipid droplets, the rate of triglyceride digestion would be very slow because of the small surface-area-to-volume ratio of these big fat droplets. The rate of digestion is, however, substantially increased by division of the large lipid droplets into many very small droplets, each about 1 mm in diameter, thereby increasing their surface area and accessibility to lipase action. This process is known as emulsification, and the resulting suspension of small lipid droplets is called an emulsion.

 The emulsification of fat requires (1) mechanical disruption of the large lipid droplets into smaller droplets and (2) an emulsifying agent, which acts to prevent the smaller droplets from reaggregating back into large droplets. The mechanical disruption is provided by the motility of the GI tract, occurring in the lower portion of the stomach and in the small intestine, which grinds and mixes the luminal contents. Phospholipids in food, along with phospholipids and bile salts secreted in the bile, provide  the emulsifying agents. Phospholipids are amphipathic molecules consisting of two nonpolar fatty acid chains attached to glycerol, with a charged phosphate group located on glycerol’s third carbon. Bile salts are formed from cholesterol in the liver and are also amphipathic. The nonpolar portions of the phospholipids and bile salts associate with the nonpolar interior of the lipid droplets, leaving the polar portions exposed at the water surface. There, they repel other lipid droplets that are similarly coated with these emulsifying agents, thereby preventing their reaggregation into larger fat droplets. The coating of the lipid droplets with these emulsifying agents, however, impairs the accessibility of the water-soluble pancreatic lipase to its lipid substrate. To overcome this problem, the pancreas secretes a protein known as colipase, which is amphipathic and lodges on the lipid droplet surface. Colipase binds the lipase enzyme, holding it on the surface of the lipid droplet.

Absorption Although emulsification speeds up digestion, absorption of the water-insoluble products of the lipase reaction would still be very slow if it were not for a second action of the bile salts, the formation of micelles, which are similar in structure to emulsion droplets but much smaller—4 to 7 nm in diameter. Micelles consist of bile salts, fatty acids, monoglycerides, and phospholipids all clustered together with the polar ends of each molecule oriented toward the micelle’s surface and the nonpolar portions forming the micelle’s core. Also included in the core of the micelle are small amounts of fat-soluble vitamins and cholesterol.

The average daily intake of lipids is 70 to 100 g per day in a typical American diet, most of this in the form of fat (triglycerides). This represents about one-third of the average daily caloric intake.

 Although fatty acids and monoglycerides enter epithelial cells from the intestinal lumen, triglycerides are released on the other side of the cell into the interstitial fluid. In other words, during their passage through the epithelial cells, fatty acids and monoglycerides are resynthesized into triglycerides. This occurs in the smooth endoplasmic reticulum, where the enzymes for triglyceride synthesis are located. This process decreases the concentration of cytosolic free fatty acids and monoglycerides and thereby maintains a diffusion gradient for these molecules into the cell from the intestinal lumen. The resynthesized fat aggregates into small droplets coated with amphipathic proteins that perform an emulsifying function similar to that of bile salts.  The exit of these fat droplets from the cell follows the same pathway as a secreted protein. Vesicles containing the droplet pinch off the endoplasmic reticulum, are processed through the Golgi apparatus, and eventually fuse with the plasma membrane, releasing the fat droplet into the interstitial fluid. These 1-microndiameter, extracellular fat droplets are known as chylomicrons. Chylomicrons contain not only triglycerides but other lipids (including phospholipids, cholesterol, and fat-soluble vitamins) that have been absorbed by the same process that led to fatty acid and monoglyceride movement into the epithelial cells of the small intestine. The chylomicrons released from the epithelial cells pass into lacteals—lymphatic vessels in the intestinal villi—rather than into the blood capillaries. The chylomicrons cannot enter the blood capillaries because the basement membrane (an extracellular glycoprotein layer) at the outer surface of the capillary provides a barrier to the diffusion of large chylomicrons. In contrast, the lacteals have large pores between their endothelial cells that allow the chylomicrons to pass into the lymph. The lymph from the small intestine, as from everywhere else in the body, eventually empties into veins.

HCL PRODUCTION AND SECRETION

The stomach secretes about 2 L of hydrochloric acid per day. The concentration of H⁺ in the lumen of the stomach may reach >150 mM, which is 1 to 3 million times greater than the concentration in the blood. This requires an efficient production mechanism to generate large numbers of hydrogen ions. The origin of the hydrogen ions is CO₂ in the parietal cell, which contains the enzyme carbonic anhydrase.  Carbonic anhydrase catalyzes the reaction between CO2 with water to produce carbonic acid, which dissociates to H⁺ and HCO3^-. Primary H⁺/K⁺-ATPases in the apical membrane of the parietal cells pump these hydrogen ions into the lumen of the stomach. This primary active transporter also pumps K⁺ into the cell, which then leaks back into the lumen through K⁺ channels. As H⁺ is secreted into the lumen, HCO3^- is secreted on the opposite side of the cell in exchange for Cl^-, which maintains electroneutrality. Removal of the end products (H⁺ and HCO3^-) of this reaction enhances the rate of the reaction by the law of mass action. In this way, production and secretion of H⁺ are coupled. Increased acid secretion results from the transfer of H⁺/K⁺-ATPase proteins from the membranes of intracellular vesicles to the plasma membrane by fusion of these vesicles with the apical membrane, thereby increasing the number of pump proteins in the apical plasma membrane. This process is analogous to the transfer of water channels (aquaporins) to the apical plasma membrane of kidney collecting-duct cells in response to ADH. 

Three chemical messengers stimulate the insertion of H⁺/K⁺-ATPases into the plasma membrane and therefore acid secretion: gastrin (a gastric hormone), acetylcholine (ACh, a neurotransmitter), and histamine (a paracrine substance). By contrast, somatostatin—another paracrine substance—inhibits acid secretion. Parietal cell membranes contain receptors for all four of these molecules. This illustrates the general principle of physiology that most physiological functions—in this case, the secretion of H⁺ into the stomach lumen—are controlled by multiple regulatory systems, often working in opposition. These chemical messengers not only act directly on the parietal cells but also influence each other’s secretion. For example, histamine markedly potentiates the response to the other two stimuli, gastrin and ACh, and gastrin and ACh both stimulate histamine secretion. During a meal, the rate of acid secretion increases markedly as stimuli arising from the cephalic, gastric, and intestinal phases alter the release of the four chemical messengers described in the previous paragraph. During the cephalic phase, increased activity of efferent parasympathetic neural input to the stomach’s enteric nervous system results in the release of ACh from the plexus neurons, gastrin from the gastrin-releasing G cells, and histamine from ECL cells.

Once food has reached the stomach, the gastric phase stimuli—distension from the volume of ingested material and the presence of peptides and amino acids released by the digestion of luminal proteins—produce a further increase in acid secretion. These stimuli use some of the same neural pathways used during the cephalic phase. Neurons in the mucosa of the stomach respond to these luminal stimuli and send action potentials to the cells of the enteric nervous system, which in turn can relay signals to the gastrin-releasing cells, histamine-releasing cells, and parietal cells. In addition, peptides and amino acids can act directly on the gastrin-releasing enteroendocrine cells to promote gastrin secretion. The concentration of acid in the gastric lumen is itself an important determinant of the rate of acid secretion because H⁺ (acid) directly inhibits gastrin secretion. It also stimulates the release of somatostatin from D cells in the stomach wall. Somatostatin then acts on the parietal cells to inhibit acid secretion; it also inhibits the release of gastrin and histamine. The net result is a negative feedback control of acid secretion. As the contents of the gastric lumen become more acidic, the stimuli that promote acid secretion decrease.

Increasing the protein content of a meal increases acid secretion.  This occurs for two reasons. First, protein ingestion increases the concentration of peptides in the lumen of the stomach. These peptides, as we have seen, stimulate acid secretion through their actions on gastrin. The second reason is more complicated and reflects the effects of proteins on luminal acidity. During the cephalic phase, before food enters the stomach, the H⁺ concentration in the lumen increases because there are few buffers present to bind any secreted H⁺. Thereafter, the rate of acid secretion soon decreases because high acidity reflexively inhibits acid secretion. The protein in food is an excellent buffer, however, so as it enters the stomach, the H⁺ concentration decreases as H⁺ binds to proteins and begins to denature them. This decrease in acidity removes the inhibition of acid secretion. The more protein in a meal, the greater the buffering of acid and the more acid secreted. We now come to the intestinal phase that controls acid secretion—the phase in which stimuli in the early portion of the small intestine influence acid secretion by the stomach. High acidity in the duodenum triggers reflexes that inhibit gastric acid secretion. This inhibition is beneficial because the digestive activity of enzymes and bile salts in the small intestine is strongly inhibited by acidic solutions. This reflex limit gastric acid production when the H⁺ concentration in the duodenum increases due to the entry of chyme from the stomach.

Acid, distension, hypertonic solutions, solutions containing amino acids, and fatty acids in the small intestine reflexively inhibit gastric acid secretion. The extent to which acid secretion is inhibited during the intestinal phase varies, depending upon the amounts of these substances in the intestine; the net result is the same, however—balancing the secretory activity of the stomach with the digestive and absorptive capacities of the small intestine. The inhibition of gastric acid secretion during the intestinal phase is mediated by short and long neural reflexes and by hormones that inhibit acid secretion by influencing the four signals that directly control acid secretion: ACh, gastrin, histamine, and somatostatin. The hormones released by the intestinal tract that reflexively inhibit gastric activity are collectively called enterogastrones and include secretin and CCK.

Control of HCl Secretion during a Meal

Secretion of hydrochloric acid by parietal cells. The H⁺ secreted into the lumen by primary active transport is derived from H⁺ generated by the reaction between carbon dioxide and water, a reaction catalyzed by the enzyme carbonic anhydrase, which is present in high concentrations in parietal cells. The HCO₃^- formed by this reaction is transported out of the parietal cell on the blood side in exchange for Cl^-.

Chyme: Semifluid mass of partially digested food expelled from stomach to intestine.

Chyle: It is a milky body fluid containing lymph and emulsified fat or free fattyacids. It is taken up by lymphatic vessels known as lacteals.

Enteroendocrine Cells

Enteroendocrine cells are the hormone-secreting cells in GI tract. These are the nerve cells and glandular cells which are present in the gastric mucosa, intestinal mucosa and the pancreatic cells.

Neuroendocrine Cells or APUD Cells

Enteroendocrine cells which secrete hormones from amines are known as amine precursor uptake and decarboxylation cells (APUD cells) or neuroendocrine cells.  For the synthesis of GI hormones, firs a precursor substance of an amine is taken up by these cells. Later, this precursor substance is decarboxylated to form the amine. From this amine, the hormone is synthesized. Because of the uptake of the amine precursor and decarboxylation of this precursor substance, these cells are called APUD cells. This type of cells is also present in other parts of the body, particularly the brain, lungs and the endocrine glands.

Structure of the alimentary canal in longitudinal section.

Defecation: Release of feces.

Mass movement drives the feces into sigmoid or pelvic colon. In the sigmoid colon, the feces is stored. The desire for defecation occurs when some feces enters rectum due to the mass movement. Usually, the desire for defecation is elicited by an increase in the intrarectal pressure to about 20 to 25 cm H2O. Usual stimulus for defecation is intake of liquid like coffee or tea or water. But it differs from person to person.

Act of Defecation

Act of defecation is preceded by voluntary efforts like assuming an appropriate posture, voluntary relaxation of external sphincter and the compression of abdominal contents by voluntary contraction of abdominal muscles. Usually, the rectum is empty. During the development of mass movement, the feces is pushed into rectum and the defecation reflex is initiated. The process of defecation involves the contraction of rectum and relaxation of internal and external anal sphincters. Internal anal sphincter is made up of smooth muscle and it is innervated by parasympathetic nerve fibers via pelvic nerve. External anal sphincter is composed of skeletal muscle and it is controlled by somatic nerve fibers, which pass through pudendal nerve. Pudendal nerve always keeps the external sphincter   constricted and the sphincter can relax only when the pudendal nerve is inhibited.

ISOSMOTIC ABSORPTION OF WATER

Water is transported through the intestinal membrane entirely by diffusion. Furthermore, this diffusion obeys the usual laws of osmosis. Therefore, when the chyme is dilute enough, water is absorbed through the intestinal mucosa into the blood of the villi almost entirely by osmosis.  Conversely, water can also be transported in the opposite direction—from plasma into the chyme. This type of transport occurs especially when hyperosmotic solutions are discharged from the stomach into the duodenum. Within minutes, sufficient water usually will be transferred by osmosis to make the chyme isosmotic with the plasma.

Absorption of iron. Fe³⁺ is converted to Fe²⁺ by ferric reductase, and Fe²⁺ is transported into the enterocyte by the apical membrane iron transporter DMT1. Heme is transported into the enterocyte by a separate heme transporter (HT), and HO2 releases Fe²⁺ from the heme. Some of the intracellular Fe²⁺ is converted to Fe³⁺ and bound to ferritin. The rest binds to the basolateral Fe²⁺ transporter ferroportin (FP) and is transported to the interstitial fluid. The transport is aided by hephaestin (Hp). In plasma, Fe²⁺ is converted to Fe³⁺ and bound to the iron transport protein transferrin (TF). Divalent metal transporter 1 (DMT1)

Calcium Absorption

A total of 30–80% of ingested calcium is absorbed. Through vitamin D derivative, Ca2+ absorption is adjusted to body needs; absorption is increased in the presence of Ca2+ deficiency and decreased in the presence of Ca2+ excess. Ca2+ absorption is also facilitated by protein. It is inhibited by phosphates and oxalates because these anions form insoluble salts with Ca2+ in the intestine. Magnesium absorption is also facilitated by protein.

Vitamins Absorption

The fat-soluble vitamins A, D, E, and K are ingested as esters and must be digested by cholesterol esterase prior to absorption. These vitamins are also highly insoluble in the gut, and their absorption is therefore entirely dependent on their incorporation into micelles. Most vitamins are absorbed in the upper small intestine, but vitamin B 12 is absorbed in the ileum. This vitamin binds to intrinsic factor, a protein secreted by the parietal cells of the stomach, and the complex is absorbed across the ileal mucosa.  Vitamin B 12 absorption and folate absorption are Na⁺ -independent, but all seven of the remaining water-soluble vitamins—thiamin, riboflavin, niacin, pyridoxine, pantothenate, biotin, and ascorbic acid—are absorbed by carriers that are Na⁺ cotransporters.

EXCRETORY SYSTEM

STRUCTURE OF KIDNEY

The two kidneys lie in the back of the abdominal wall but not actually in the abdominal cavity. They are retroperitoneal, meaning they are just behind the peritoneum, the lining of this cavity. The urine flows from the kidneys through the ureters into the bladder and then is eliminated via the urethra. The major structural components of the kidney are shown in the figure. The indented surface of the kidney is called the hilum, through which courses the blood vessels perfusing (renal artery) and draining (renal vein) the kidneys. The nerves that

innervate the kidney and the tube that drains urine from the kidney (the ureter) also pass through the hilum. The ureter is formed from the calyces (singular, calyx), which are funnel-shaped structures that drain urine into the renal pelvis, from where the urine enters the ureter. Also notice that the kidney is surrounded by a protective capsule made of connective tissue. The kidney is divided into an outer renal cortex and inner renal medulla, described in more

detail later. The connection between the tip of the medulla and the calyx is called the papilla.

Each kidney contains approximately 1 million similar functional units called nephrons. Each nephron consists of (1) an initial filtering component called the renal corpuscle and (2) a tubule that extends from the renal corpuscle. The renal tubule is a very narrow, fluid-filled cylinder made up of a single layer of epithelial cells resting on a basement membrane. The epithelial cells differ in structure and function along the length of the tubule, and at least eight distinct segments are now recognized. It is customary, however, to group two or more contiguous tubular segments when discussing function, and we will follow this practice. The renal corpuscle forms a filtrate from blood that is free of cells, larger polypeptides, and proteins. This filtrate then leaves the renal corpuscle and enters the tubule. As it flows through the tubule, substances are added to or removed from it. Ultimately, the fluid remaining at the end of each nephron combines in the collecting ducts and exits the kidneys as urine.

FUNCTIONS OF KIDNEYS

The kidneys perform their most important functions by filtering the plasma and removing substances from the filtrate at variable rates, depending on the needs of the body. Ultimately, the kidneys “clear” unwanted substances from the filtrate (and therefore from the blood) by excreting them in the urine while returning substances that are needed back to the blood.

Although this chapter and the next few chapters focus mainly on the control of renal excretion of water, electrolytes, and metabolic waste products, the kidneys serve many important homeostatic functions, including the following:

• Excretion of metabolic waste products and foreign chemicals

• Regulation of water and electrolyte balances

• Regulation of body fluid osmolality and electrolyte concentrations

• Regulation of arterial pressure

• Regulation of acid-base balance

• Regulation of erythrocyte production

• Secretion, metabolism, and excretion of hormones

• Gluconeogenesis

Excretion of Metabolic Waste Products, Foreign Chemicals, Drugs, and Hormone Metabolites. The kidneys are the primary means for eliminating waste products of metabolism that are no longer needed by the body. These products include urea (from the metabolis of amino acids), creatinine (from muscle creatine), uric acid (from nucleic acids), end products of hemoglobin breakdown (such as bilirubin), and metabolites of various hormones. These waste products must be eliminated from the body as rapidly as they are produced. The kidneys also eliminate most toxins and other foreign substances that are either produced by the body or ingested, such as pesticides, drugs, and food additives.

Regulation of Water and Electrolyte Balances. For maintenance of homeostasis, excretion of water and electrolytes must precisely match intake. If intake exceeds excretion, the amount of that substance in the body will increase. If intake is less than excretion, the amount of that substance in the body will decrease. Although temporary (or cyclic) imbalances of water and electrolytes may occur in various physiological and pathophysiological conditions associated with altered intake or renal excretion, the maintenance of life depends on restoration of water and electrolyte balance. Intake of water and many electrolytes is governed mainly by a person’s eating and drinking habits, requiring the kidneys to adjust their excretion rates to match the intakes of various substances. The figure shows the response of the kidneys to a sudden 10-fold increase in sodium intake from a low level of 30 mEq/day to a high level of 300 mEq/day. Within 2 to 3 days after raising the sodium intake, renal excretion also increases to about 300 mEq/day so that a balance between intake and output is rapidly re-established. However, during the 2 to 3 days of renal adaptation to the high sodium intake, there is a modest accumulation of sodium that raises extracellular fluid volume slightly and triggers hormonal changes and other compensatory responses that signal the kidneys to increase their sodium excretion. The capacity of the kidneys to alter sodium excretion in response to changes in sodium intake is enormous. Experimental studies have shown that in many people, sodium intake can be increased to 1500 mEq/day (more than 10 times normal) or decreased to 10 mEq/day (less than one-tenth normal) with relatively small changes in extracellular fluid volume or plasma sodium concentration. This phenomenon is also true for water and for most other electrolytes, such as chloride, potassium, calcium, hydrogen, magnesium, and phosphate ions. In the next few chapters, we discuss the specific mechanisms that permit the kidneys to perform these amazing feats of homeostasis.

Regulation of Arterial Pressure. The kidneys play a dominant role in long-term regulation of arterial pressure by excreting variable amounts of sodium and water. The kidneys also contribute to short-term arterial pressure regulation by secreting hormones and vasoactive factors or substances (e.g., renin) that lead to the formation of vasoactive products (e.g., angiotensin II).

Regulation of Acid-Base Balance. The kidneys contribute to acid-base regulation, along with the lungs and body fluid buffers, by excreting acids and by regulating the body fluid buffer stores. The kidneys are the only means of eliminating from the body certain types of acids, such as sulfuric acid and phosphoric acid, generated by the metabolism of proteins.

Regulation of Erythrocyte Production. The kidneys secrete erythropoietin, which stimulates the production of red blood cells by hematopoietic stem cells in the bone marrow. One important stimulus for erythropoietin secretion by the kidneys is hypoxia. The kidneys normally account for almost all the erythropoietin secreted into the circulation. In people with severe kidney disease or who have had their kidneys removed and have been placed on hemodialysis, severe anemia develops as a result of decreased erythropoietin production.

Regulation of 1,25-Dihydroxyvitamin D3 Production.

The kidneys produce the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), by hydroxylating this vitamin at the “number 1” position. Calcitriol is essential for normal calcium deposition in bone and calcium reabsorption by the gastrointestinal tract. Calcitriol plays an important role in calcium and phosphate regulation.

Glucose Synthesis. The kidneys synthesize glucose from amino acids and other precursors during prolonged fasting, a process referred to as gluconeogenesis. The kidneys’ capacity to add glucose to the blood during prolonged periods of fasting rivals that of the liver. With chronic kidney disease or acute failure of the kidneys, these homeostatic functions are disrupted and severe abnormalities of body fluid volumes and composition rapidly occur. With complete renal failure, enough potassium, acids, fluid, and other substances accumulate in the body to cause death within a few days, unless clinical interventions such as hemodialysis are initiated to restore, at least partially, the body fluid and electrolyte balances.

STRUCTURE OF NEPHRON

The nephron is the functional unit of the kidney responsible for the formation of urine. Each kidney contains more than a million nephrons. A nephron consists of small tubes, or tubules, and associated small blood vessels. Fluid formed by capillary filtration enters the tubules and is subsequently modified by transport processes; the resulting fluid that leaves the tubules is urine.

Renal Blood Vessels

Arterial blood enters the kidney through the renal artery, which divides into interlobar arteries that pass between the pyramids through the renal columns. Arcuate arteries branch from the interlobar arteries at the boundary of the cortex and medulla. A number of interlobular arteries radiate from the arcuate arteries into the cortex and subdivide into numerous afferent arterioles, which are microscopic. The afferent arterioles deliver blood into glomeruli — capillary networks that produce a blood filtrate that enters the urinary tubules. The blood remaining in a glomerulus leaves through an efferent arteriole, which delivers the blood into another capillary network—the peritubular capillaries surrounding the renal tubules.

This arrangement of blood vessels is unique. It is the only one in the body in which a capillary bed (the glomerulus) is drained by an arteriole rather than by a venule and delivered

to a second capillary bed located downstream (the peritubular capillaries). Blood from the peritubular capillaries is drained into veins that parallel the course of the arteries in the kidney. These veins are called the interlobular veins, arcuate veins, and interlobar veins. The interlobar veins descend between the pyramids, converge, and leave the kidney as a single renal vein, which empties into the inferior vena cava.

Nephron Tubules

The tubular portion of a nephron consists of a glomerular capsule, a proximal convoluted tubule, a descending limb of the loop of Henle, an ascending limb of the loop of Henle, and a distal convoluted tubule. The glomerular (Bowman’s) capsule surrounds the glomerulus. The glomerular capsule and its associated glomerulus are located in the cortex of the kidney and together constitute the renal corpuscle. The glomerular capsule contains an inner visceral layer of epithelium around the glomerular capillaries and an outer parietal layer. The space between these two layers is continuous with the lumen of the tubule and receives the glomerular filtrate, as will be described in the next section.

Filtrate that enters the glomerular capsule passes into the lumen of the proximal convoluted tubule. The wall of the proximal convoluted tubule consists of a single layer of cuboidal cells containing millions of microvilli; these microvilli increase the surface area for reabsorption. In the process of reabsorption, salt, water, and other molecules needed by the body are transported from the lumen, through the tubular cells and into the surrounding peritubular capillaries.

The glomerulus, glomerular capsule, and convoluted tubule are located in the renal cortex. Fluid passes from the proximal convoluted tubule to the nephron loop, or loop of Henle. This fluid is carried into the medulla in the descending limb of the loop and returns to the cortex in the ascending limb of the loop. Back in the cortex, the tubule again becomes coiled and is called the distal convoluted tubule.

The distal convoluted tubule is shorter than the proximal tubule and has relatively few microvilli. The distal convoluted tubule terminates as it empties into a collecting duct. The two principal types of nephrons are classified according to their position in the kidney and the lengths of their loops of Henle. Nephrons that originate in the inner one-third of the cortex—called juxtamedullary nephrons because they are next to the medulla—have longer loops of Henle than the more numerous cortical nephrons, which originate in the outer two-thirds of the cortex. The juxtamedullary nephrons play an important role in the ability of the kidney to produce a concentrated urine. A collecting duct receives fluid from the distal convoluted tubules of several nephrons. Fluid is then drained by the collecting duct from the cortex to the medulla as the collecting duct passes through a renal pyramid. This fluid, now called urine, passes into a minor calyx. Urine is then funneled through the renal pelvis and out of the kidney in the ureter.

URINE FORMATION

Urine formation begins with the filtration of plasma from the glomerular capillaries into Bowman’s space. This process is termed glomerular filtration, and the filtrate is called the glomerular filtrate. It is cell-free and, except for larger proteins, contains all the substances in virtually the same concentrations as in plasma. This type of filtrate, in which only low-molecular weight solutes appear, is also called an ultrafiltrate. During its passage through the tubules, the filtrate’s composition is altered by movements of substances from the tubules to the peritubular capillaries, and vice versa. When the direction of movement is from tubular lumen to peritubular capillary plasma, the process is called tubular reabsorption or, simply, reabsorption. Movement in the opposite direction—that is, from peritubular plasma to tubular lumen—is called tubular secretion or, simply, secretion. Tubular secretion is also used to denote the movement of a solute from the cell interior to the lumen in the cases in which the kidney tubular cells themselves generate the substance.   In a day 180L/day filtrate formed but 99% of them were reabsorbed only 1 – 2 L/day is formed as urine.

To summarize, a substance can gain entry to the tubule and be excreted in the urine by glomerular filtration or tubular secretion or both. Once in the tubule, however, the substance does not have to be excreted but can be partially or completely reabsorbed. Thus, the amount of any substance excreted in the urine is equal to the amount filtered plus the amount secreted minus the amount reabsorbed.

Urine flow through the ureters to the bladder is propelled by contractions of the ureter wall smooth muscle. The urine is stored in the bladder and intermittently ejected during urination, or micturition.

Incontinence is the involuntary release of urine, which can be a disturbing problem both socially and hygienically. The most common types are stress incontinence (due to sneezing, coughing, or exercise) and urge incontinence (associated with the desire to urinate). Incontinence is more common in women and may occur one to two times per week in more than 25% of women older than 60. It is very common in older women in nursing homes and assisted-living facilities

Glomerular filtration

Urine formation begins when a large amount of fluid that is virtually free of protein is filtered from the glomerular capillaries into Bowman’s capsule. Most substances in the plasma, except for proteins, are freely filtered, so their concentration in the glomerular filtrate in Bowman’s capsule is almost the same as in the plasma.  As stated previously, the glomerular filtrate—that is, the fluid in Bowman’s space—normally contains no cells but contains all plasma substances except proteins in virtually the same concentrations as in plasma. This is because glomerular filtration is a bulk-flow process in which water and all low-molecular-weight substances (including smaller polypeptides) move together. Most plasma proteins—the albumins and globulins—are excluded from the filtrate in a healthy kidney. One reason for their exclusion is that the renal corpuscles restrict the movement of such highmolecular-weight substances. A second reason is that the filtration pathways in the corpuscular membranes are negatively charged, so they oppose the movement of these plasma proteins, most of which are also negatively charged.

The only exceptions to the generalization that all nonprotein plasma substances have the same concentrations in the glomerular filtrate as in the plasma are certain low-molecular-weight substances that would otherwise be filterable but are bound to plasma proteins and therefore not filtered. For example, the half of the plasma calcium bound to plasma proteins and virtually all of the plasma fatty acids that are bound to plasma protein are not filtered.

The volume of fluid filtered from the glomeruli into Bowman’s space per unit time is known as the glomerular filtration rate (GFR). Starling forces are (1) the hydrostatic pressure difference across the capillary wall that favors filtration and (2) the protein concentration difference across the wall that creates an osmotic force that opposes filtration.  The range of GFR is 90 – 140 ml/min for men and 80 – 125 ml/min for women.  The range with respect to day is 180L/day for men and 170L/day for women.

Tubular Reabsorption

Recall that a major function of the kidneys is to eliminate soluble waste products. To do this, the blood is filtered in the glomeruli. One consequence of this is that substances necessary for normal body functions are filtered from the plasma into the tubular fluid. To prevent the loss of these important nonwasted products, the kidneys have powerful mechanisms to reclaim useful substances from tubular fluid while simultaneously allowing waste products to be excreted. The reabsorptive rates for water and many ions, although also very high, are under physiological control. For example, if water intake is decreased, the kidneys can increase water reabsorption to minimize water loss. In contrast to glomerular filtration, the crucial steps in tubular reabsorption—those that achieve movement of a substance from tubular lumen to interstitial fluid—do not occur by bulk flow because there are inadequate pressure differences across the tubule and limited permeability of the tubular membranes. Instead, two other processes are involved. (1) The reabsorption of some substances from the tubular lumen is by diffusion, often across the tight junctions connecting the tubular epithelial cells. (2) The reabsorption of all other substances involves mediated transport, which requires the participation of transport proteins in the plasma membranes of tubular cells. The final step in reabsorption is the movement of substances from the interstitial fluid into peritubular capillaries that occurs by a combination of diffusion and bulk flow.

Reabsorption by Diffusion The reabsorption of urea by the proximal tubule provides an example of passive reabsorption by diffusion. An analysis of urea concentrations in the proximal tubule will help clarify the mechanism. As stated earlier, urea is a waste product; however, as you will learn shortly, some urea is reabsorbed from the proximal tubule in a process that facilitates water reabsorption farther down the nephron. Because the corpuscular

membranes are freely filterable to urea, the urea concentration in the fluid within Bowman’s space is the same as that in the peritubular capillary plasma and the interstitial fluid surrounding the tubule. Then, as the filtered fluid flows through the proximal tubule, water reabsorption occurs (by mechanisms to be described later). This removal of water increases the concentration of urea in the tubular fluid so it is higher than in the interstitial fluid and peritubular capillaries. Therefore, urea diffuses down this concentration gradient from tubular lumen to peritubular capillary. Urea reabsorption is thus dependent upon the reabsorption of water.

Reabsorption by Mediated Transport Many solutes are reabsorbed by primary or secondary active transport. These substances must first cross the apical membrane (also called the luminal membrane) that separates the tubular lumen from the cell interior. Then, the substance diffuses through the cytosol of the cell and, finally, crosses the basolateral membrane, which begins at the tight junctions and constitutes the plasma membrane of the sides and base of the cell. The movement by this route is termed transcellular epithelial transport. A substance does not need to be actively transported across both the apical and basolateral membranes in order to be actively transported across the overall epithelium, moving from lumen to interstitial fluid against its electrochemical gradient. For example, Na⁺ moves “downhill” (passively) into the cell across the apical membrane through specific channels or transporters and then is actively transported “uphill” out of the cell across the basolateral membrane via Na⁺/K⁺-ATPases in this membrane. The reabsorption of many substances is coupled to the reabsorption of Na⁺. The cotransported substance moves uphill into the cell via a secondary active cotransporter as Na⁺ moves downhill into the cell via this same cotransporter. This is precisely how glucose, many amino acids, and other organic substances undergo tubular reabsorption. The reabsorption of several inorganic ions is also coupled in a variety of ways to the reabsorption of Na⁺. Many of the mediated-transport-reabsorptive systems in the renal tubule have a limit to the amounts of material they can transport per unit time known as the transport maximum (Tm). This is because the binding sites on the membrane transport proteins become saturated when the concentration of the transported substance increases to a certain level. An important example is the secondary active-transport proteins for glucose, located in the proximal tubule.

The pattern described for glucose is also true for a large number of other organic nutrients. For example, most amino acids and water-soluble vitamins are filtered in large amounts each day, but almost all of these filtered molecules are reabsorbed by the proximal tubule. If the plasma concentration becomes high enough, however, reabsorption of the filtered load will not be as complete and the substance will appear in larger amounts in the urine. Thus, people who ingest very large quantities of vitamin C have increased plasma concentrations of vitamin C. Eventually, the filtered load may exceed the tubular reabsorptive Tm for this substance, and any additional ingested vitamin C is excreted in the urine.

Tubular Secretion

Tubular secretion moves substances from peritubular capillaries into the tubular lumen. Like glomerular filtration, it constitutes a pathway from the blood into the tubule. Like reabsorption, secretion can occur by diffusion or by transcellular mediated transport. The most important substances secreted by the tubules are H⁺ and K⁺. However, a large number of normally occurring organic anions, such as choline and creatinine, are also secreted; so are many foreign chemicals such as penicillin. Active secretion of a substance requires active transport either from the blood side (the interstitial fluid) into the tubule cell (across the basolateral membrane) or out of the cell into the lumen (across the apical membrane). As in reabsorption, tubular secretion is usually coupled to the reabsorption of Na⁺. Secretion from the interstitial space into the tubular fluid, which draws substances from the peritubular capillaries, is a mechanism to increase the ability of the kidneys to dispose of substances at a higher rate rather than depending only on the filtered load.

Metabolism by the Tubules

We noted earlier that, during fasting, the cells of the renal tubules synthesize glucose and add it to the blood. They can also catabolize certain organic substances, such as peptides, taken up from either the tubular lumen or peritubular capillaries. Catabolism eliminates these substances from the body just as if they had been excreted into the urine.

Counter Current Mechanism

Counter current system:

System in renal medulla that facilitates concentration of urine as it passes through renal tubules.  Counter current multiplier is an active process responsible for osmotic gradient to produce concentrated urine. It is otherwise called as positive feedback mechanism. Counter current exchanger refers to the exchange of material between two flowing bodies. 

The following progression of steps will occur:

1. The interstitial fluid is now a little hypertonic due to the NaCl pumped out of the ascending limb.

2. Because of the slightly hypertonic interstitial fluid, some water leaves the descending limb by osmosis (and enters the blood) as the filtrate goes deeper into the medulla. This makes the filtrate somewhat hypertonic when it reaches the ascending limb.

3. The now higher NaCl concentration of the filtrate that enters the ascending limb allows it to pump out more NaCl than it did before, because more NaCl is now available to the carriers. The interstitial fluid now becomes yet more concentrated.

4. Because the interstitial fluid is more concentrated than it was in step 2, more water is drawn out of the descending limb by osmosis, making the filtrate even more hypertonic when it reaches the ascending limb.

5. Step 3 is repeated, but to a greater extent because of the higher NaCl concentration delivered to the ascending limb.

6. This progression continues until the maximum concentration is reached in the inner medulla. This maximum is determined by the capacity of the active transport pumps working along the lengths of the thick segments of the ascending limbs.