Pathophysiology
of Acute Diarrhea
HENRYJ. BINDER,M.D. New Haven, Connectmt
Diarrhea, a major health problem worldwide, is both a sign and a symptom. As a symptom, diarrhea has been described as an increase in stool frequency, an increase in stool volume, and/or a decrease in stool consistency. As a sign, diarrhea is characterized by an increase in stool water excretion to greater than 150 to 200 ml every 24 hours. Four mechanisms that may be responsible for the alterations in fluid and electrolyte movement associated with diarrhea are increased luminal osmolality, decreased fluid absorption, increased intestinal secretion, and altered intestinal motility. Specific pathogenic mechanisms for acute infectious diarrhea include tissue invasion, enterotoxin production, and adhesion of infectious agents to epithelial cells. Antidiarrheal agents remove secretagogues from the intestinal tract, stimulate fluid absorption, and inhibit electrolyte movement.
lthough it is known that diarrhea is a major A health problem in developing countries, the incidence of acute diarrhea in the United States is difficult to determine. Despite the common occurrence of diarrhea, it is a “closet condition,” one that is rarely discussed and often self-treated. It is thought that the majority of affected persons experience limited disability, whereas a minority suffer considerable debilitation, affecting both lifestyle and productivity. It is important to remember that diarrhea is both a symptom and a sign. As a symptom, diarrhea can be described as an increase in stool frequency, an increase in stool volume, and/or a decrease in stool consistency. As a sign, diarrhea is defined objectively as an increase in stool water excretion to an amount greater than 150 to 200 ml every 24 hours. As either a sign or a symptom, diarrhea can be classified according to several parameters: duration (acute versus chronic), affected organ (small intestine, large intestine, or both), clinical description (frequency, volume, consistency, presence of blood), origin, and primary pathophysiologic mechanism. Although this list may not be definitive, it can help the physician to obtain information useful for diagnosis and treatment.
NORMALBOWELFUNCTION
From the Department of Medicine, Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Dr. Henry J. Binder, Yale University School of Medicine, 333 Cedar Street, 92 LMP, New Haven, Connecticut 06510.
6A-2S
June 20, 1990
The American Journal of Medicine
To better understand the pathophysiology of acute diarrhea, one must first be familiar with normal bowel function. A clinical study of normal bowel function was conducted among 5,000 British factory workers more than 20 years ago [l]. When the workers were asked to report their number of bowel movements, the range was from two or three bowel movements per day to two or three per week. Assuming that one can generalize from these data to the American population, one can see that daily frequency is not necessarily a measure of normal bowel function. Normal fluid and electrolyte movement are inextricably linked to normal bowel function. Approximately 6 to 8 liters of fluid enter the jejunum in 24 hours. Only 1.5 liters are contributed from the diet; the remainder of the overall fluid load is made up of gastric, salivary, pancreatic, and biliary secretions. Ileocecal flow is approximately 1.5 to 2 liters per day; therefore, the small intestine is absorbing approximately ‘75 percent of the fluid to which it is exposed. In contrast, the colon absorbs approximately 1.5 to 2 liters of fluid per day, whereas less than 100 to 200 ml per day of stool water is absorbed. The maximal absorptive capacity of the colon is 4.5 to 5 liters per day. Because the colon absorbs over 90 percent of the fluid to which it is exposed, the colon is a more efficient absorptive organ than the small intestine. If there is a decrease in small intestinal fluid absorption, regardless of cause, diarrhea will not develop until the absorptive capacity of the colon is exceeded. On the other hand, relatively small decreases in co-
Volume 88 (suppl 6A)
SYMPOSIUM
ionic absorption can lead to substantial increases in stool water excretion, and diarrhea will result.
MECHANISMSOF DIARRHEA Although most discussions of diarrhea are concerned with water excretion, it is important to bear in mind that all gastrointestinal water flow is a result of solute movement. Water absorption is secondary to solute absorption, and water secretion follows solute secretion-largely secretion of sodium and chloride. Therefore, information on the body’s ability to absorb and secrete sodium and chloride is crucial to the understanding of cellular events in acute diarrhea. During the past 20 years, several investigators have measured fluid movement directly in healthy subjects and in those with a variety of diarrhea1 disorders [2-51. These studies were conducted in healthy persons with normal fluid and electrolyte absorption in whom a segment of intestine was perfused with isotonic saline solution. When a similar maneuver is performed in subjects with a variety of diarrhea1 diseases, it can be demonstrated that fluid and electrolytes are secreted from the jejunum, ileum, or colon. Several mechanisms may account for these alterations in fluid movement; these include increased luminal osmolality, decreased fluid absorption, increased intestinal secretion, and altered intestinal motility. Increased Osmolality
Primary lactase deficiency is an example of a disease in which diarrhea is a result of increased luminal osmolality [6]. Lactase, a brush-border enzyme of the small intestine, is absent from the intestinal mucosa in people with this disease. In the presence of colonic bacteria, dietary lactose is not absorbed, leading to the formation of a variety of short-chain fatty acids, carbon dioxide, and hydrogen. The resulting increase in luminal osmolality causes altered fluid movement and diarrhea. Decreased Fluid Absorption
Diminished absorption of fluid and electrolytes is often secondary to mucosal damage in either the small or the large intestine. Celiac sprue is the prototypical disease in which there is substantial mucosal abnormality. Normal jejunal villi are absent, surface epithelial cells are altered, and crypt height is increased. Diarrhea that occurs in persons with celiac sprue can be attributed, in part, to a substantial decrease in mucosal absorptive function, and is primarily a consequence of the histologic abnormalities and mucosal inflammation present in the jejunum.
ON MANAGEMENT
OF ACUTE DIARRHEA/BINDER
movement. For example, in Escherichia coli toxigenie diarrhea, an acute diarrhea1 illness, one mechanism is stimulation of active chloride secretion by the E. coli heat labile (or LT) enterotoxin and, in turn, this chloride secretion stimulates excess fluid secretion. The enterotoxins, however, do not usually cause structural damage to the small intestine nor alter absorptive function. Hormones that increase intestinal secretion include vasoactive intestinal peptide, serotonin, and calcitonin. Prostaglandin El, which stimulates adenylate cyclase and increases mucosal cyclic adenosine monophosphate levels, has recently been implicated as the mediator of diarrhea in ulcerative colitis. Diarrhea also has been noted as an adverse effect of prostaglandin administration. Although vasoactive intestinal peptide affects ion transport by increasing intracellular cyclic adenosine monophosphate levels, other secretagogues (e.g., serotonin) alter ion transport by acting as a calcium ionophore. Altered Intestinal Motility
The mechanism by which fluid and electrolyte movement is affected by alterations in intestinal motility is not clearly understood. The precise relations between changes in motor function, changes in intraluminal pressure, changes between intraluminal pressure, and intestinal transit time need to be clarified.
ACUTEDIARRHEA:PATHOPHYSIOLOGY For purposes of this discussion, acute diarrhea will be equated with infectious diarrhea. When describing infectious diarrhea1 illness, heterogeneity is the hallmark. One sees substantial variation, not only in origin and clinical presentation, but also in pathophysiolx-Y* Tissue invasion-by Shigella or certain invasive strains of E. coli-represents one pathophysiologic mechanism. Giardia is also known to be an invasive organism, but whether fluid production is directly related to the invasion remains controversial. Ingestion of a preformed enterotoxin, as in staphylococcal food poisoning, is another mechanism. In situ production of the enterotoxin following ingestion of the organism, as with E. coli and Vibrio cholerae, can also occur. Adhesion of E. coli to epithelial cells without associated invasion or enterotoxin production is a third mechanism in acute diarrhea. Finally, there is recent research evidence that the Shiga-like toxin produced by E. coli may be yet another cause of acute diarrhea.
Increased Intestinal Secretion
ANTIDIARRHEAL AGENTS:MECHANISMSOF ACTION
Active electrolyte secretion is the third mechanism causing alterations in fluid and electrolyte movement. Agents that stimulate secretion, known as secretagogues, may be present in the small and large intestine. They are heterogeneous and frequently responsible for several diarrhea1 disorders [3,4,7]. Intestinal secretagogues can be classified into three groups: bacterial enterotoxins, hormones (either circulating or present as paracrine mediators), and detergents (including bile acids, fatty acids, and commercial laxatives). All of the secretagogues stimulate active chloride secretion, thus affecting sodium and chloride
Because of an increased understanding of the pathophysiology of diarrhea, the mechanisms of action of antidiarrheal agents are becoming clearer. Three general principles of drug therapy can be identified [8]. Since many diarrhea1 disorders are associated with the presence of a secretagogue, the first principle is removal of the secretagogue. Frequently this is not a possibility, but it is sometimes feasible. For example, when “bile acid diarrhea” or cholerheic enteropathy is present, cholestyramine can be administered to bind the bile acid. This effectively removes the secretagogue from its target organ.
June 20, 1990
The Amencan Journal of Medicine
Volume 88 (suppl 6A)
6A-3s
SYMF’OSIUMON MANAGEMENTOF ACUTEDIARRHEA/ BINDER
The second general principle is stimulation of fluid absorption. If the absorptive capacity of the small or large intestine is operating at less than maximum, one may effectively increase fluid absorption in an attempt to maintain hydration and decrease stool output. The use of glucose in so-called oral rehydration solutions, clonidine and other alpha, adrenergic agonists, and glucocorticosteroids are all effective based on this principle [g-11]. Inhibition of electrolyte secretion is the third principle, and phenothiazines have been studied to achieve this therapeutic goal [12]. New light has been shed on the mechanisms of action of newer antidiarrheal agents such as loperamide hydrochloride [13]. These studies have shown that the primary benefit of loperamide is its ability to affect motility, increasing mucosal contact time and resulting in greater fluid absorption. In addition to prolonging transit time and effectively increasing fluid absorption, this agent inhibits secretory processes, thereby decreasing stool water excretion.
COMMENTS Once normal bowel function is understood, it becomes clear that abnormal electrolyte and fluid movement can result in acute diarrhea. The mechanisms responsible for these alterations in fluid movement correspond directly to the modes of action of effective antidiarrheal agents: removal of the secretagogue, stimulation of fluid absorption, and inhibition of electrolyte secretion. As knowledge of the pathophysiolo-
6A-4!4
June 20, 1990
The American Journal of Medicine
gic mechanisms of diarrhea becomes even more sophisticated, investigators will better understand why certain antidiarrheal agents and therapies are safer and more effective than others.
REFERENCES 1. Connell AM, Hilton C, Irvine G, et a/; Variations in bowel habits in two population samples. Br Med J 1965; 2: 1095-1099. 2 Binder HJ: Net fluid and electrolyte secretion: the pathophysiologic basis of diarrhea. In: Binder HJ. ed. Mechanism of intestinal secretion. New York Alan R Liss Inc.. 1979: 1-15. 3. BinderHJ: Absorption and secretion of water and electrolyte by small and large intestine. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal diseases, 3rd ed. Philadelphia: WB Saunders Co., 1983; 811-829. A Donowitz M, Welsh MJ: Regulation of mammalian small intestinal electrolyte secretion. In: Johnson LR, ed. Physiology of the gastrointestinal tract, 2nd ed. New York Raven Press, 1987; 1351-1388. 5. Krejs G, Fordtran JS: Diarrhea. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal diseases, 3rd ed. Philadelphia: WB Saunders Co. 1983; 257-280. 6. Christopher NL, Bayless TM: Role of the small bowel and colon in lactose-induced diarrhea. Gastroenteroloav 1971: 69: 845-852. 7. Dobbins JW, Binder Hx Pathophysiologv of diarrhea: alterations in fluid and eletrolyte transport. Clin Gastroenterol 1981; 10: 605-625. 8. Binder HJ: New approaches to antidiarrheal therapy. In: Lebenthal E, ed. Chronic diarrhea in children. New York: Raven Press, 1984; 437-443. 9. Sandle GI. Havslett JP. Binder HJ: The effect of nlucocorticosteroids on rectal transoort in normal subjects and patients with ulcerative &is. Gut 1986; 27: 309-316. 10. McArthur K, Anderson D, Durbin T, et at Clonidine and lidamidine inhibit watery diarrhea in a patient with lung cancer, Ann Intern Med 1982; 96: 323-325. 11. Kraenzlin ME, Ch’ng JLC, Wood SM, et al: Long-term treatment of a VlPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985; 88: 185-187. 12 Donowitz M, Elta G, Bloom SR, et at Triiuoperazine reversal of secretory diarrhea in pancreatic cholera. Ann Intern Med 1980; 93: 284-285. 13. Schiller LR, Santa Ana CA, Morawski SG, eta/; Mechanism of the antidiarrheal effect of loperamide. Gastroenterology 1984; 86: 1475-1483.
Volume 88 (suppl 6A)
of Acute Diarrhea
HENRYJ. BINDER,M.D. New Haven, Connectmt
Diarrhea, a major health problem worldwide, is both a sign and a symptom. As a symptom, diarrhea has been described as an increase in stool frequency, an increase in stool volume, and/or a decrease in stool consistency. As a sign, diarrhea is characterized by an increase in stool water excretion to greater than 150 to 200 ml every 24 hours. Four mechanisms that may be responsible for the alterations in fluid and electrolyte movement associated with diarrhea are increased luminal osmolality, decreased fluid absorption, increased intestinal secretion, and altered intestinal motility. Specific pathogenic mechanisms for acute infectious diarrhea include tissue invasion, enterotoxin production, and adhesion of infectious agents to epithelial cells. Antidiarrheal agents remove secretagogues from the intestinal tract, stimulate fluid absorption, and inhibit electrolyte movement.
lthough it is known that diarrhea is a major A health problem in developing countries, the incidence of acute diarrhea in the United States is difficult to determine. Despite the common occurrence of diarrhea, it is a “closet condition,” one that is rarely discussed and often self-treated. It is thought that the majority of affected persons experience limited disability, whereas a minority suffer considerable debilitation, affecting both lifestyle and productivity. It is important to remember that diarrhea is both a symptom and a sign. As a symptom, diarrhea can be described as an increase in stool frequency, an increase in stool volume, and/or a decrease in stool consistency. As a sign, diarrhea is defined objectively as an increase in stool water excretion to an amount greater than 150 to 200 ml every 24 hours. As either a sign or a symptom, diarrhea can be classified according to several parameters: duration (acute versus chronic), affected organ (small intestine, large intestine, or both), clinical description (frequency, volume, consistency, presence of blood), origin, and primary pathophysiologic mechanism. Although this list may not be definitive, it can help the physician to obtain information useful for diagnosis and treatment.
NORMALBOWELFUNCTION
From the Department of Medicine, Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Dr. Henry J. Binder, Yale University School of Medicine, 333 Cedar Street, 92 LMP, New Haven, Connecticut 06510.
6A-2S
June 20, 1990
The American Journal of Medicine
To better understand the pathophysiology of acute diarrhea, one must first be familiar with normal bowel function. A clinical study of normal bowel function was conducted among 5,000 British factory workers more than 20 years ago [l]. When the workers were asked to report their number of bowel movements, the range was from two or three bowel movements per day to two or three per week. Assuming that one can generalize from these data to the American population, one can see that daily frequency is not necessarily a measure of normal bowel function. Normal fluid and electrolyte movement are inextricably linked to normal bowel function. Approximately 6 to 8 liters of fluid enter the jejunum in 24 hours. Only 1.5 liters are contributed from the diet; the remainder of the overall fluid load is made up of gastric, salivary, pancreatic, and biliary secretions. Ileocecal flow is approximately 1.5 to 2 liters per day; therefore, the small intestine is absorbing approximately ‘75 percent of the fluid to which it is exposed. In contrast, the colon absorbs approximately 1.5 to 2 liters of fluid per day, whereas less than 100 to 200 ml per day of stool water is absorbed. The maximal absorptive capacity of the colon is 4.5 to 5 liters per day. Because the colon absorbs over 90 percent of the fluid to which it is exposed, the colon is a more efficient absorptive organ than the small intestine. If there is a decrease in small intestinal fluid absorption, regardless of cause, diarrhea will not develop until the absorptive capacity of the colon is exceeded. On the other hand, relatively small decreases in co-
Volume 88 (suppl 6A)
SYMPOSIUM
ionic absorption can lead to substantial increases in stool water excretion, and diarrhea will result.
MECHANISMSOF DIARRHEA Although most discussions of diarrhea are concerned with water excretion, it is important to bear in mind that all gastrointestinal water flow is a result of solute movement. Water absorption is secondary to solute absorption, and water secretion follows solute secretion-largely secretion of sodium and chloride. Therefore, information on the body’s ability to absorb and secrete sodium and chloride is crucial to the understanding of cellular events in acute diarrhea. During the past 20 years, several investigators have measured fluid movement directly in healthy subjects and in those with a variety of diarrhea1 disorders [2-51. These studies were conducted in healthy persons with normal fluid and electrolyte absorption in whom a segment of intestine was perfused with isotonic saline solution. When a similar maneuver is performed in subjects with a variety of diarrhea1 diseases, it can be demonstrated that fluid and electrolytes are secreted from the jejunum, ileum, or colon. Several mechanisms may account for these alterations in fluid movement; these include increased luminal osmolality, decreased fluid absorption, increased intestinal secretion, and altered intestinal motility. Increased Osmolality
Primary lactase deficiency is an example of a disease in which diarrhea is a result of increased luminal osmolality [6]. Lactase, a brush-border enzyme of the small intestine, is absent from the intestinal mucosa in people with this disease. In the presence of colonic bacteria, dietary lactose is not absorbed, leading to the formation of a variety of short-chain fatty acids, carbon dioxide, and hydrogen. The resulting increase in luminal osmolality causes altered fluid movement and diarrhea. Decreased Fluid Absorption
Diminished absorption of fluid and electrolytes is often secondary to mucosal damage in either the small or the large intestine. Celiac sprue is the prototypical disease in which there is substantial mucosal abnormality. Normal jejunal villi are absent, surface epithelial cells are altered, and crypt height is increased. Diarrhea that occurs in persons with celiac sprue can be attributed, in part, to a substantial decrease in mucosal absorptive function, and is primarily a consequence of the histologic abnormalities and mucosal inflammation present in the jejunum.
ON MANAGEMENT
OF ACUTE DIARRHEA/BINDER
movement. For example, in Escherichia coli toxigenie diarrhea, an acute diarrhea1 illness, one mechanism is stimulation of active chloride secretion by the E. coli heat labile (or LT) enterotoxin and, in turn, this chloride secretion stimulates excess fluid secretion. The enterotoxins, however, do not usually cause structural damage to the small intestine nor alter absorptive function. Hormones that increase intestinal secretion include vasoactive intestinal peptide, serotonin, and calcitonin. Prostaglandin El, which stimulates adenylate cyclase and increases mucosal cyclic adenosine monophosphate levels, has recently been implicated as the mediator of diarrhea in ulcerative colitis. Diarrhea also has been noted as an adverse effect of prostaglandin administration. Although vasoactive intestinal peptide affects ion transport by increasing intracellular cyclic adenosine monophosphate levels, other secretagogues (e.g., serotonin) alter ion transport by acting as a calcium ionophore. Altered Intestinal Motility
The mechanism by which fluid and electrolyte movement is affected by alterations in intestinal motility is not clearly understood. The precise relations between changes in motor function, changes in intraluminal pressure, changes between intraluminal pressure, and intestinal transit time need to be clarified.
ACUTEDIARRHEA:PATHOPHYSIOLOGY For purposes of this discussion, acute diarrhea will be equated with infectious diarrhea. When describing infectious diarrhea1 illness, heterogeneity is the hallmark. One sees substantial variation, not only in origin and clinical presentation, but also in pathophysiolx-Y* Tissue invasion-by Shigella or certain invasive strains of E. coli-represents one pathophysiologic mechanism. Giardia is also known to be an invasive organism, but whether fluid production is directly related to the invasion remains controversial. Ingestion of a preformed enterotoxin, as in staphylococcal food poisoning, is another mechanism. In situ production of the enterotoxin following ingestion of the organism, as with E. coli and Vibrio cholerae, can also occur. Adhesion of E. coli to epithelial cells without associated invasion or enterotoxin production is a third mechanism in acute diarrhea. Finally, there is recent research evidence that the Shiga-like toxin produced by E. coli may be yet another cause of acute diarrhea.
Increased Intestinal Secretion
ANTIDIARRHEAL AGENTS:MECHANISMSOF ACTION
Active electrolyte secretion is the third mechanism causing alterations in fluid and electrolyte movement. Agents that stimulate secretion, known as secretagogues, may be present in the small and large intestine. They are heterogeneous and frequently responsible for several diarrhea1 disorders [3,4,7]. Intestinal secretagogues can be classified into three groups: bacterial enterotoxins, hormones (either circulating or present as paracrine mediators), and detergents (including bile acids, fatty acids, and commercial laxatives). All of the secretagogues stimulate active chloride secretion, thus affecting sodium and chloride
Because of an increased understanding of the pathophysiology of diarrhea, the mechanisms of action of antidiarrheal agents are becoming clearer. Three general principles of drug therapy can be identified [8]. Since many diarrhea1 disorders are associated with the presence of a secretagogue, the first principle is removal of the secretagogue. Frequently this is not a possibility, but it is sometimes feasible. For example, when “bile acid diarrhea” or cholerheic enteropathy is present, cholestyramine can be administered to bind the bile acid. This effectively removes the secretagogue from its target organ.
June 20, 1990
The Amencan Journal of Medicine
Volume 88 (suppl 6A)
6A-3s
SYMF’OSIUMON MANAGEMENTOF ACUTEDIARRHEA/ BINDER
The second general principle is stimulation of fluid absorption. If the absorptive capacity of the small or large intestine is operating at less than maximum, one may effectively increase fluid absorption in an attempt to maintain hydration and decrease stool output. The use of glucose in so-called oral rehydration solutions, clonidine and other alpha, adrenergic agonists, and glucocorticosteroids are all effective based on this principle [g-11]. Inhibition of electrolyte secretion is the third principle, and phenothiazines have been studied to achieve this therapeutic goal [12]. New light has been shed on the mechanisms of action of newer antidiarrheal agents such as loperamide hydrochloride [13]. These studies have shown that the primary benefit of loperamide is its ability to affect motility, increasing mucosal contact time and resulting in greater fluid absorption. In addition to prolonging transit time and effectively increasing fluid absorption, this agent inhibits secretory processes, thereby decreasing stool water excretion.
COMMENTS Once normal bowel function is understood, it becomes clear that abnormal electrolyte and fluid movement can result in acute diarrhea. The mechanisms responsible for these alterations in fluid movement correspond directly to the modes of action of effective antidiarrheal agents: removal of the secretagogue, stimulation of fluid absorption, and inhibition of electrolyte secretion. As knowledge of the pathophysiolo-
6A-4!4
June 20, 1990
The American Journal of Medicine
gic mechanisms of diarrhea becomes even more sophisticated, investigators will better understand why certain antidiarrheal agents and therapies are safer and more effective than others.
REFERENCES 1. Connell AM, Hilton C, Irvine G, et a/; Variations in bowel habits in two population samples. Br Med J 1965; 2: 1095-1099. 2 Binder HJ: Net fluid and electrolyte secretion: the pathophysiologic basis of diarrhea. In: Binder HJ. ed. Mechanism of intestinal secretion. New York Alan R Liss Inc.. 1979: 1-15. 3. BinderHJ: Absorption and secretion of water and electrolyte by small and large intestine. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal diseases, 3rd ed. Philadelphia: WB Saunders Co., 1983; 811-829. A Donowitz M, Welsh MJ: Regulation of mammalian small intestinal electrolyte secretion. In: Johnson LR, ed. Physiology of the gastrointestinal tract, 2nd ed. New York Raven Press, 1987; 1351-1388. 5. Krejs G, Fordtran JS: Diarrhea. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal diseases, 3rd ed. Philadelphia: WB Saunders Co. 1983; 257-280. 6. Christopher NL, Bayless TM: Role of the small bowel and colon in lactose-induced diarrhea. Gastroenteroloav 1971: 69: 845-852. 7. Dobbins JW, Binder Hx Pathophysiologv of diarrhea: alterations in fluid and eletrolyte transport. Clin Gastroenterol 1981; 10: 605-625. 8. Binder HJ: New approaches to antidiarrheal therapy. In: Lebenthal E, ed. Chronic diarrhea in children. New York: Raven Press, 1984; 437-443. 9. Sandle GI. Havslett JP. Binder HJ: The effect of nlucocorticosteroids on rectal transoort in normal subjects and patients with ulcerative &is. Gut 1986; 27: 309-316. 10. McArthur K, Anderson D, Durbin T, et at Clonidine and lidamidine inhibit watery diarrhea in a patient with lung cancer, Ann Intern Med 1982; 96: 323-325. 11. Kraenzlin ME, Ch’ng JLC, Wood SM, et al: Long-term treatment of a VlPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985; 88: 185-187. 12 Donowitz M, Elta G, Bloom SR, et at Triiuoperazine reversal of secretory diarrhea in pancreatic cholera. Ann Intern Med 1980; 93: 284-285. 13. Schiller LR, Santa Ana CA, Morawski SG, eta/; Mechanism of the antidiarrheal effect of loperamide. Gastroenterology 1984; 86: 1475-1483.
Volume 88 (suppl 6A)
