Notes

45. The fetus derives its oxygen from the maternal arterial blood supply by gas exchange across the placenta. The umbilical vein draining the placenta, therefore has the highest oxygenation in the fetus, with a PO2 of ~30 mmHg and 80% oxygen saturation. The ductus venosus has only a slightly lower PO2, and serves to direct much of the highly oxygenated blood from the umbilical vein to the inferior vena cava, bypassing the liver. From the right atrium, about two-thirds of the inferior venal caval flow (67% O2 saturation) is diverted across the foramen ovale to the left atrium. The PO2 in the left ventricular outflow tract going to the ascending aorta is ~25 mmHg. The PO2 in the ductus arteriosus is ~18 mmHg, and blood in the descending aorta and umbilical arteries, is ~20 mmHg with an oxygen saturation of ~60%.

46. Contractile activity in the small intestine is initiated in response to distention of the bowel

wall. Three types of smooth muscle contractions contribute to small intestinal motility—peristalsis, segmental contractions, and tonic contractions. A fourth type of contraction, peristaltic rushes, are very intense peristaltic waves that may occur in intestinal obstruction. The basal electrical

rhythm (BER) are the spontaneous rhythmic fluctuations in membrane potential in the smooth muscle along the GI tract. The BER itself rarely causes muscle contraction, but contractions only occur during the depolarizing phase of BERs, which function to coordinate the various types of

contractile activity. The BER is initiated by the interstitial cells of Cajal, which, in the small intestine, are located in the outer circular muscle layer near the myenteric plexus. There are an average of ~12 BER cycles/min in the duodenum and proximal jejunum and 8/min in the distal ileum. During fasting between periods of digestion, cycles of motor activity, called migrating motor complexes (MMC), migrate from the stomach to the distal ileum. The MMCs immediately stop with ingestion of food. After vagotomy, contractile activity becomes irregular and chaotic.

47. Increases in basal and maximal acid output are suggestive of inflammation or removal of the proximal small intestine. Intestinal receptors monitor the composition of chyme and elicit feedback mechanisms that regulate gastric acid secretion and gastric emptying. Absence of feedback leads to an increased presence of excitatory mediators of gastric function. Gastrin is the primary stimulus of meal-induced acid secretion by the parietal cells. Somatostatin (paracrine), secretin (endocrine), and enterogastrone (endocrine) inhibit gastric acid secretion by the parietal cells. Histamine is an excitatory paracrine mediator of parietal cell acid secretion.

48. Orad stomach accommodation depends exclusively on an intact vago-vagal reflex. Vagal innervation of the gastrointestinal tract extends from the esophagus to the level of the transverse colon. Preganglionic fibers from cell bodies in the medulla synapse with ganglion cells located in the enteric nervous system. Distention-induced contraction of gastrointestinal smooth muscle devel-

ops as the result of long (vago-vagal) and local (enteric nerves) reflexes. The importance of long versus local reflex pathways varies along the gut. Secondary esophageal peristalsis, intestinal segmentation, and migrating motor complexes are unaffected by vagotomy, whereas caudad stomach peristalsis is decreased but not abolished by vagotomy.

Increases in intragastric volume normally are not associated with large increases in intragastric

pressure because of distention-mediated activation of a vago-vagal inhibitory reflex, called receptive relaxation or the accommodation reflex. The reflex, which is abolished by vagotomy, is a property of the orad stomach only and counterbalances the stretch-induced myogenic contraction of the gastric smooth muscle. Peristalsis, trituration (grinding), and retropulsion (mixing) are terms referring to the contractile activity and functions of the caudad stomach. Segmental contractions are the primary contractile pattern of the small intestine during the digestive period.

49. Histamine (H2) receptor antagonists inhibit both gastrin-induced and vagal-mediated secretion of acid. Secretion of acid by gastric parietal (oxyntic) cells involves stimulation of adenyl cyclase and cyclic AMP-mediated stimulation of the active transport of chloride and potassium-hydrogen ion exchange. Neither gastrin nor vagal stimulation activates adenyl cyclase directly; both depend on concomitant release of histamine and histamine-induced activation of adenyl cyclase.

50. Inflammation or removal of the upper small intestine leads to a decrease in pancreatic and

hepatobiliary function. The proximal small intestine contains a number of “receptors” that monitor the physical (volume) and chemical (pH, fat content, caloric density, osmolality) composition of the chyme emptied from the stomach. Stimulation of these receptors releases secretin, which acts on

pancreatic ductal cells to increase HCO3–secretion, as well as cholecystokinin, which acts on pancreatic acinar cells to increase pancreatic enzyme secretion (lipases, amylases, and proteases). Stimulation of proximal small intestine receptors also activates neural reflexes, which initiate pancreatic enzyme and bicarbonate secretion, stimulate gallbladder emptying, and provide feedback for inhibitory regulation of gastric function (enterogastrone, enterogastric reflex). Removal of these reflexes decreases pancreatic secretion and gallbladder emptying and increases gastric emptying and acid output.

51. Inflammation of the duodenum may lead to increased acid output, hypocalcemia, and microcytic anemia. Increased basal and maximal acid outputs may result from excessive stimulation of the parietal cell (e.g., hypergastrinemia) or reduced inhibitory feedback (i.e., reduced effect of enterogastrone and the enterogastric reflex). The latter may occur when the proximal small intestine is inflamed. Although calcium is absorbed along the entire length of the small intestine, it is absorbed primarily in the duodenum. Similarly, iron is absorbed primarily in the duodenum. Micro-

cytic anemia is the result of reduced stores of iron, the most common anemia. Glucose-6-phosphatase deficiency is the most common metabolic disorder of red blood cells, and is also associated with a microcytic anemia, as is α-thalassemia.

52. Removal of the terminal ileum can lead to diarrhea and steatorrhea. The ter-

minal ileum contains specialized cells responsible for the absorption of pri-

mary and secondary bile salts by active transport. Bile salts are necessary for

adequate digestion and absorption of fat. In the absence of the terminal ileum

there will be an increase in the amounts of bile acids and fatty acids delivered

to the colon. Fats and bile salts in the colon increase the water content of the

feces by promoting the influx (secretion) of water into the lumen of the

colon. Amino acids are absorbed in the jejunum. Iron is primarily absorbed

in the duodenum.

Gastrointestinal neuroendocrine tumors are derived from

the diffuse neuroendocrine system of the GI tract, which is composed of

amine- and acid-producing cells with different hormonal profiles, depending

on the site of origin. The tumors they produce are generally divided into car-

cinoid tumors (ectodermal stem cells) and pancreatic endocrine tumors. One

third of all primary gut tumors are carcinoid. Carcinoid tumors are fre-

quently classified according to their anatomic area of origin (foregut, midgut,

hindgut). Small intestinal (midgut) carcinoid tumors arise from the argentaf-

fin cells of the crypts of Lieberkühn in the terminal ileum, and have a high

serotonin content. Small intestinal carcinoids are the most common cause of

the carcinoid syndrome (classic triad: cutaneous flushing, diarrhea, bron-

chospasm, right heart valvular lesions), which is manifest when they metas-

tasize, but only occurs in 5 to 10% of carcinoid tumors.

53. Both the absorption of Na+ and secretion of K+ from the colon are affected by changes in circulating levels of aldosterone. The major route of absorption of sodium in the colon is electrogenic transport. Because of the “tight” nature of the tight junctions that connect cells in the colon, a relatively large potential difference exists between the mucosal (negative) and serosal (positive) surfaces of the absorptive cells. This electrical difference favors the net secretion of K+

into the lumen. Secretion of HCO3– occurs in exchange for absorption of Cl–. No counterbalancing cation exchange pumps are present in the colon.

54. Although only small amounts of bile acids are lost in the stool each day, the loss represents the only route of elimination of cholesterol from the body. The predominant organic component of bile is the bile salts, which make up about 67% of the total solutes. Bile salts are amphiphilic molecules, that is, they exhibit both water and lipid solubility. Primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized from cholesterol. Secondary bile acids, deoxycholic acid and lithocholic acid, are produced by biotransformation of primary bile acids by intestinal bacteria. Prior to secretion, the bile acids are conjugated with either glycine or taurine, which greatly enhances their water solubility. In general, taurine conjugates are more water-soluble than glycine conjugates.

55. Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw fluid into the lumen of the small intestine or colon leading to osmotic water loss in the stool. In osmotic diarrhea, the stool osmotic gap (290 – 2[Na++ K+]) exceeds 50 mOsm, consistent with an unmeasured solute contributing to the fecal electrolyte content. Osmotic diarrhea generally ceases with fasting or discontinued ingestion of the solute. The most common causes of osmotic diarrhea are (1) lactase (and other disaccharide) deficiency with resultant lactose intolerance and carbohydrate malabsorption, (2) ingestion of magnesium-containing antacids or laxatives, and (3) ingestion of nonabsorbable sugars, such as sorbitol.

Secretory diarrhea, on the other hand, is caused by the overproduction of water by the small and large bowel. Crypt cell secretion of an isosmotic chloride solution increases combined with inhibition of electroneutral NaCl absorption from the small intestine. In contrast to osmotic diarrhea, secretory diarrhea has a normal stool osmotic gap and is not remedied with fasting. The other major patho-physiologic mechanisms of chronic diarrhea include steatorrheal, inflammatory, infectious, dysmotile, radiation injury, and factitial causes.

56. The transport protein responsible for the sodium-dependent glucose transport in the small

intestine is termed the SGLT1 (Na+-glucose transporter). The absorption of glucose occurs through the coordinated action of transport proteins located in the brush border and basolateral membranes of the enterocyte. Glucose uptake into the enterocyte from the lumen of the GI tract occurs primarily via the sodium-dependent SGLT1 secondary active transport mechanism. Glucose exit from the enterocyte into the extracellular fluid occurs by facilitated diffusion and is mediated by the membrane transporter, Glut-2. The Na+ glucose cotransporter also transports galactose. Thus, when the cotransporter is congenitally defective, the resulting glucose and galactose malabsorption causes severe diarrhea that can be fatal if glucose and galactose are not removed from the diet. A similar secondary active transport process (Na+-glucose cotransport) occurs in the renal tubules via SGLT1 and SGLT2. Glut-5 is the membrane transporter located on the apical portion of the enterocyte responsible for the facilitated entry of fructose into the cell.

57. The colon is the major site for the generation and absorption of short-chain fatty acids. They are products of bacterial metabolism of undigested complex carbohydrates derived from fruits and vegetables. In addition to exhibiting trophic effects on the colonic mucosa, they are believed to pro-

mote sodium absorption from the colon. The mechanism of action remains controversial.

58. Medium-chain triglycerides are hydrolyzed by lipases more rapidly than long-chain fatty acids and are much more water-soluble than long-chain triglycerides. Medium-chain triglycerides (MCTs) are fatty acids of 6 to 12 carbon chain lengths that are present in small amounts in the normal diet. MCTs are not utilized for resynthesis of triglycerides and therefore are not packaged into chylomicrons. Instead, they are released directly into the portal blood. Because they are readily absorbed, MCTs can be used in patients with a wide variety of GI diseases resulting in malabsorption.

Long-chain fatty acids are extruded from enterocytes in the form of chylomicrons into the lymphatic system. Triglycerides are hydrolyzed to monoglycerides and taken into mucosal cells. If the fatty acids are short chains (less than 10 to 12 carbon atoms), they are extruded in the form of free fatty acids into the portal blood. Chylomicrons represent triglycerides and esters of cholesterol that have been invested in the intestinal mucosa with a coating of phospholipid, protein, and cholesterol.

58. Iron is transported in the blood bound to the β-globulin, transferrin. Excess iron is stored in all cells, but especially in hepatocytes where it combines with apoferritin. The stored form is called ferritin. The rate of iron absorption is extremely slow, with a maximum of only a few milligrams per day. Iron is absorbed primarily in the ferrous form. Therefore, ferrous iron compounds, rather than ferric compounds, are effective in treating iron deficiency.

59. Somatostatin, located within the gastric antral mucosa, is the principal paracrine secretion involved in the inhibitory feedback of gastric acid secretion by parietal cells. Somatostatin has a short half-life of several minutes, which limits its clinical use, but the analog octreotide (Sandostatin) should be administered subcutaneously to inhibit the secretion of gastrin and gastric

acid and visceral blood flow in patients with bleeding esophageal varices secondary to portal hypertension, after stabilizing with IV fluids, as acute variceal bleeds have a 50% mortality.

Acid secretion is stimulated by acetylcholine (via M3 muscarinic receptors), histamine (via H2 receptors) and gastrin (directly via gastrin receptors and principally via stimulation of histamine secretion by enterochromaffin-like [ECL] cells). Gastrin secretion is stimulated by the amino acids and peptides produced by pepsin’s action in protein digestion.

60. Liberation of the enzyme enteropeptidase (enterokinase) from the duodenal mucosal cells

causes the inactive trypsinogen to be converted to the active form, trypsin. Enteropeptidase contains 41% polysaccharide. It is this high level of polysaccharide that protects enteropeptidase from digestion. Trypsin is responsible for the conversion of chymotrypsinogens and other proenzymes into their active forms.

61. One of the actions of colonic bacteria is to convert NH3 to NH4+. Thus, a total colectomy would increase blood ammonia levels, which would be exacerbated in a person with cirrhosis. NH3 is in equilibrium with NH4+. Most of the NH4+ formed by oxidative deamination of amino acids in the liver is converted to urea, and the urea is excreted in the urine. The NH4+ forms carbamoyl phosphate, and in the mitochondria it is transferred to ornithine by ornithine carbamoyl-transferase forming citrulline. Citrulline is converted to arginine, after which urea is split off and ornithine is regenerated (urea cycle). Most of the urea is formed in the liver, and in severe liver disease the blood urea nitrogen falls and blood NH3 rises.

Normally, about 5 to 10% of bile salts enter the colon. In the colon, bacteria convert the two primary bile acids, cholic acid and chenodeoxycholic acid to the secondary bile acids, deoxycholic acid and lithocholic acid, respectively. Lithocholate is relatively insoluble and is mostly excreted in the stool, but deoxycholate is reabsorbed from the colon, where it is transported back to the liver in the portal vein and reexcreted in the bile (enterohepatic circulation).

Humans can survive after total removal of the colon if fluid and electrolyte balance is maintained. When total colectomy is performed, the ileum is brought out through the abdominal wall

(ileostomy). Advances in surgical techniques make ileostomies relatively trouble-free and patients with them can lead essentially normal lives.

62. The bilirubin in serum represents a balance between input from production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or removal of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts.

Alkaline phosphatase, which is excreted in bile, increases in patients with jaundice due to bile duct obstruction, but generally not when the jaundice is due to hepatocellular disease. Bile acids are synthesized in the liver by a series of enzymatic steps that also involve cholesterol catabolism. Liver disease decreases bile acid synthesis.

63. Clearance is a measure of how much plasma is totally cleared of a substance. It is calculated using the formul

Clearance = Uuric acid × V/Puric acid = 36 mg/dL × 1 mL/min / 0.6 mg/dL

= 60 mL/min

Urine volume = 1 mL/min

Urine uric acid = 36 mg/dL

serum uric acid concentration (0.6 mg/dL)

Free Water Clearance (CH2O) = V ˙− Cosmolar

Cosmolar = Uosm × V ˙/Posm , where Uosm = 2 × (UNa+ + UK+)

CH2O = V ˙– [2 (UNa+ + UK+) × V ˙/Posm

CH2O = 1 L/day − [2 (125 mM + 25 mM) × 1 L/day] / 2 × 125 mM

CH2O = − 0.2 L/day