CASE 32 A 17-year-old boy presents to his primary care physician with complaints of diarrhea for the last 2 days. The patient states that he just returned to the United States after visiting relatives in Mexico. The diarrhea began suddenly and is described as water. He has noticed no abdominal pain or blood in his stool. On examination, he appears dehydrated, but otherwise his physical examination is normal. His stool is examined and appears like rice water. The patient is diagnosed with an infectious form of diarrhea, most likely due to Vibrio cholerae. What location in the gastrointestinal (GI) tract has tight, or impermeable, junctions between the epithelial cells? Why do patients with diarrhea often have hypokalemia? How does V. cholerae cause diarrhea?
266 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 32: INTESTINAL WATER AND ELECTROLYTE TRANSPORT Summary: A 17-year-old boy has profuse watery diarrhea from a V. cholerae infection. Location of impermeable gap junctions: Large intestine. Hypokalemia with diarrhea: Intestinal secretions are enriched in potassium, and so there is increased loss with diarrhea. V. cholerae and diarrhea: Toxin binds to receptors on apical membrane of crypt cells and activates adenylate cyclase, which increases intracellular cyclic adenosine monophosphate (camp) and secretion of chloride. Both sodium and water follow the chloride into the lumen and result in the secretory diarrhea. CLINICAL CORRELATION Diarrhea can be seen in a variety of conditions and disease processes. There are four basic mechanisms that result in diarrhea: osmotic (lactose intolerance), exudative disorders (inflammatory bowel disease), secretory (V. cholerae), and motility disturbance (hyperthyroidism). Diarrhea from cholera has a rapid onset and can lead to progressive dehydration and even death. The incubation period is about 24 to 48 hours, after which the patient will begin having painless watery diarrhea. The diarrhea is free from blood and appears like rice water. Patients often complain of muscle cramps that result from electrolyte abnormalities. Complications are a result of the fluid loss and electrolyte abnormalities. When patients are adequately hydrated and electrolytes are replaced, the process is self-limiting and resolves in a few days. The diagnosis can be confirmed by the identification of V. cholerae in stool. APPROACH TO WATER ABSORPTION Objectives 1. Discuss sodium and water absorption and secretion in the small intestine and colon. 2. Describe potassium, chloride, and bicarbonate absorption and secretion in the small intestine and colon. DISCUSSION Approximately 9 L of water and 30 g of sodium are absorbed from the small intestine and colon each day, but only about 2 L of water and 5 g of sodium are ingested. The difference between absorbed and ingested values is
CLINICAL CASES 267 because of salivary, gastric, pancreatic, biliary, and intestinal secretions, which then are reabsorbed. The vast majority of this fluid is absorbed by the small intestine, with only about 1 to 2 L being absorbed from the colon. Normally, only about 0.1 to 0.2 L is excreted in the feces. Throughout the GI tract, water permeates membranes passively to maintain isosmotic conditions (except for salivary secretions, which are hypotonic, and colonic contents, which are hypertonic) as solutes are actively secreted and absorbed. Salivary glands, the stomach, the pancreas, and the liver are mainly secretory organs, as discussed in Case 30. The intestine, in contrast, has both secretory and absorptive functions. Under normal conditions, absorption dominates, but as in this case, that is not always the case. The mechanisms involved in small intestinal absorption of the products of digestion are covered in Case 31. This absorption, which is accompanied by significant amounts of sodium, chloride, and water, is accomplished by villus epithelial cells. Intestinal secretion, by contrast, is accomplished by crypt epithelial cells. There are multiple pathways and mechanisms by which sodium is absorbed by villus cells of the intestine. The major ones are the sodium-coupled absorption of sugars and amino acids, sodium-chloride cotransport, sodium-hydrogen countertransport, and the entry of sodium by restricted diffusion. All these are secondary active processes that are powered by the sodium-potassium ATPase located on the basolateral borders of the villus cells. With this absorption comes the passive absorption of anions, mostly chloride, and water. Potassium is absorbed by both passive and active processes. In the small intestine, potassium is concentrated in the chyme as sodium and water are absorbed, but because the paracellular pathways are leaky, potassium is absorbed passively down its electrochemical gradient. In the colon, which is less leaky, potassium is absorbed through a primary active process involving a potassiumhydrogen ATPase. Potassium also is secreted actively by colonic villus cells because of the restricted diffusion of potassium through apical membrane channels. Thus, as sodium is absorbed, potassium is lost. The net result is that fecal fluid has a relatively high potassium concentration. The situation with bicarbonate is also complicated. Most of the secreted bicarbonate acts to neutralize the acid secreted by the stomach. This results in no net loss or gain of bicarbonate because the secretion of acid involves the production of bicarbonate to balance that which is secreted by the pancreas and liver. In the distal small intestine and colon, bicarbonate is secreted in exchange for chloride through the action of a chloride-bicarbonate countertransporter on the apical membrane of villus cells. Thus, fecal secretions tend to be alkaline. There normally is a low level of secretion of sodium, chloride, and water by crypt epithelial cells of the small intestine because of the secondary active transport of chloride. A sodium-potassium-chloride cotransporter is located on the basolateral surface of these cells (see Figure 32-1). Thus, the movement of sodium down its electrochemical gradient facilitates the uptake of chloride. This chloride then exits the apical membrane down its electrochemical gradient by restricted diffusion through a chloride channel. Sodium and
268 CASE FILES: PHYSIOLOGY Lumen Interstitium CI K + CI Na + Na + (K + ) CI (CI ) Na + Na + Figure 32-1. Crypt cells of the intestine. Cl is secreted by a secondary active process. water follow passively through paracellular pathways. The fluid secreted by these cells helps maintain the liquidity of the intestinal contents and aids in digestion and absorption. The activity of the chloride channel is regulated by both calcium and camp. Elevations of either caused by actions of neurotransmitters, or in this case toxins, increase flux through the channels and result in an increase in secretion. This secretion can exceed the ability of the villus cells to absorb, thus resulting in diarrhea rich in volume, potassium, and bicarbonate. Fortunately, the absorptive abilities of the villus cells are large and can be maximized by orally administering fluids that are rich in sodium and glucose. This is the basis for the oral rehydration (replacement) therapies that have been so successful in decreasing mortality from secretory diarrhea. COMPREHENSION QUESTIONS [32.1] Oral rehydration formulas are noted to facilitate the absorption of sodium chloride and water. This observation is due in particular because of the inclusion of which of the following? A. Bile salts B. Other chloride salts C. Carbohydrates D. Fatty acids E. Proteins
CLINICAL CASES 269 [32.2] Which of the following is the rank order, from greatest to least, of areas of water absorption in the GI tract in a normal individual? A. Colon, small intestine, stomach B. Colon, stomach, small intestine C. Small intestine, colon, stomach D. Small intestine, stomach, colon E. Stomach, small intestine, colon [32.3] Patients with cystic fibrosis have a defect in apical chloride channels in many epithelial cells. Such patients have a major defect in which of the following? A. Colonic sodium chloride and water absorption B. Gastric acid secretion C. Ileal bile acid absorption D. Jejunal glucose absorption E. Small intestinal sodium chloride and water secretion Answers [32.1] C. Owing to the presence of sodium-coupled glucose transporters in intestinal epithelial cells, sodium and water absorption are greatly enhanced by the inclusion of carbohydrates. Although amino acid and bile salt absorption also are sodium coupled, those transporters are not as abundant. Absorption of fatty acids is not sodium coupled. [32.2] C. By far, the greatest volume of intestinal contents is absorbed by the small intestine. The volume absorbed by the colon is significant and can increase when the functioning of the small intestine is impaired. However, the volume absorbed is much less than in the small intestine. The stomach absorbs little, if any, water. It mostly is a secretory organ. [32.3] E. Sodium, potassium, and chloride are transported actively into intestinal crypt cells across their basolateral borders. Chloride then exits the cells down its electrochemical gradient through apical chloride channels. These channels are defective in cystic fibrosis. HCl secretion by the gastric parietal cells does not involve these chloride channels. Also, the chloride that is absorbed along with sodium in the small intestine and large intestine does not pass through these channels. Bile acids are anions at the ph existing in the ileum and are not associated with chloride absorption.
270 CASE FILES: PHYSIOLOGY PHYSIOLOGY PEARLS Water absorption and secretion in the intestine are passive and are driven by the absorption and secretion of solutes. Small intestinal villus epithelial cells absorb sodium and water; villus crypt cells secrete sodium and water. The majority of water absorption takes place in the proximal small intestine and is isosmotic. Sodium absorption in the ileum and colon is partially regulated by aldosterone. If bile salts are not absorbed in the ileum and pass into the colon, they increase secretion of electrolytes and water by the colon. Loss of gastric contents by vomiting results in alkalosis because of loss of hydrochloric acid. Diarrhea results in acidosis because of loss of bicarbonate. REFERENCES Johnson LR. Intestinal electrolyte and water transport. In: Johnson LR, ed. Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:547-555. Johnson LR. Fluid and electrolyte absorption. In: Johnson LR, ed. Gastrointestinal Physiology. 7th ed. Philadelphia, PA: Mosby; 2007:127-135. Kutchai HC. Digestive system. In: Levy MN, Koeppen BM, and Stanton BA, eds. Berne & Levy, Principles of Physiology. 4th ed. Philadelphia, PA: Mosby; 2006:429-494.