Diarrhea: A Current View of the Pathophysiology

Vol. 6:1,

GASTROENTEHOLOGY

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© 1972 hy The Willi ams & Wilk ins Co.

No.~

Printed in U.S.A.

PROGRESS IN GASTROENTEROLOGY

DIARRHEA: A CURRENT VIEW OF THE PATHOPHYSIOLOGY

s.

F.

PHILLIPS,

M .D .

Gastro enterology Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

and is readily appreciated, despite inadequate statistics; among United States troops in Southeast Asia, dysenteric diseases accounted for 14% of all hospital admissions. 2 The description of diarrhea by Aretaeus needs little modification after almost 2 millenia, but a precise definition is more elusive. As it is a symptom, individual subjective variations are prominent: diarrhea is an alteration of the bowel habit of the individual.. The frequency of bowel movements in a "normal" population varies from twice daily to twice weekly. 3 The usual clinical definition is of increased frequency and/or increased fluidity of bowel movements, for the individual. Transposed into pathophysiological terms , diarrhea results from the passage of stools containing e-xcess water, i.e., malabsorption of water. Daily stool weight of healthy adults is encompassed by a range of 100 to 200 g of which 60 to 85% is water• -7 ; individuals complaining of diarrhea excrete more than 200 g of stool daily 7 containing 60 to 95% water. 5 Thus, variations of a few hundred milliliters of water are sufficient to influence the consistency and frequency of bowel movements . Since intestinal water absorption or secretion is due to passive forces , arising secondary to transport of solute, 8 it should be possible to implicate malabsorption or secretion of a fecal solute as being responsible for increased fecal water. Thus, diarrhea can be explained in terms of increased excretion of solute. Further, sodium transport is one of the major determinants of water movement in the gut 9 and certain

Diarrhea consists of the discharge of undigested food in a fluid state; (such as) when the heat does not digest the food, nor convert it into its proper chyme, but leaves its work half finished. For it is liquid and wants consistence from not being completely elaborated, and from no part of the digestive process having been properly done, except the commencement. -ARETAEUS THE CAPPADOC IAN

(2nd to 3rd Century A.D .)

The alimentary canal receives, mixes, digests, and absorbs widely variable and unpredictable amounts of food with remarkable efficiency. One striking measure of normal gastrointestinal function is the excretion of a small and convenient volume of solid waste. When the sequence comprising integrated intestinal function fails, fecal excretion is inconvenient, bulky, and liquid. The concept of intestinal failure, although not usually specified, is comparable with more generally accepted syndromes of failure in other organ systems. It is in this context that diarrhea should be considered. Episodic diarrhea occurs irregularly in most individuals without underlying chronic intestinal disease an d, based on insurance disability claims, 1 the symptom is a leading cause for absence from work, especially in women. The global significance of infectious diarrhea is great Received September 7, .1971. Address requests for reprints to: Dr. S. F. Phillips, Gastroenterology Unit, Mayo Clinic and Mayo Foundat ion, Rochester, Minneso ta 55901. Supported in part by Research Grant AM-6908 from the Na tional Institutes of Health, Bethesda, Maryl and. 495

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diarrheas may be examples of excessive sodium excretion. Indeed, a close relationship exists between fecal sodium and fecal water 8 in many types of diarrhea. In other examples, the water-soluble solute responsible for diarrhea appears to be potassium or chloride ions or unabsorbed carbohydrate molecules. For purposes of this review, fluids entering the intestinal lumen will be listed initially, for in terms of volume and solute content these greatly exceed the small changes in fecal volume that produce diarrhea. Present concepts of intestinal absorption and secretion of solute and water will then be stated briefly, followed by a classification of pathophysiological mechanisms known to result in disordered water movement. The implications of fecal analysis to the pathogenesis of diarrhea and certain principles of therapy, which follow from these basic considerations, will be summarized.

Enterosystemic cycle Diet l2L

Extra cellular fluid (12-20L)

Absorption Jej unu m (3-SL) Ileum (2 -4U Colon (1- 2 L)

(0.1-0.2Ll

FIG. 1. Circulation of diet and endogenous fluids into and out of the gut per 24 hr. TABLE 1. Approximate composition of diet and gastrointestinal secretions (per 24 hr)

Normal Physiology

Diet and Gastrointestinal Secretions: the Enterosystemic Cycle Large volumes of essentially isotonic fluid enter the lumen of the proximal bowel through diet and endogenous secretions of the upper digestive tract. Based on a daily computation, this volume of fluid exceeds the extracellular volume and is equivalent to a major proportion of total body water. However, much more than 90% of these fluids are reabsorbed, thereby completing an efficient enterosystemic cycle (fig. 1). Of these diverse inputs (table 1), diet is most readily quantified but most variable. The values listed are intended to portray the orders of magnitude that are involved. The contributions by gastrointestinal secretion predominate, commencing with saliva which provides a surprisingly large volume of fluid, estimated to be at least 1000 ml per day 10 of fluid which is hypotonic, 11 relative to other body fluids. Gastric secretion, although quantified extensively in fasting man, has only recently been assessed in response to the more natural stimulus of a meal. Rune 12 demon-

Fecal loss

Volume

dium

Potassi um

C hl oride

So-

liter

mEq

mEq

mEq

Diet .. . . .. . . .. . .. .. . . .. . . .. . .. Saliva . Gastric juice .......... . . . . . .. . . . . Bile .. . . Pancreatic juice ...... Small intestinal "suecus'' ..... . . . .. .

2 1 2 1 2

150 50 100 200 150

50 20 15 5 5

200 40 280 40 40

1

150

5

100

Total ... . . . . . . . .. . ...

9.0

800

100

700

strated, by indirect techniques, that the gastric secretory response to a normal meal approximates that to maximal histamine stimulation. Utilizing this assumption and figures for stimulated and overnight secretion, 10 a plausible figure for daily volumes of gastric secretion can be calculated. Precise figures for biliary and pancreatic secretion in response to natural stimuli are unavailable, but acceptable approximations are given. 13 The contribution made by intestinal secretions, "succus entericus," is more contentious. Early estimates were probably excessive since they were based on aspirations from ob-

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PROGRESS IN GASTROENTEROLOGY

structed bowel, 14 and the volume of t1uid discharged from defunctioned loops of bowel is small. 15 The proximal small intestine contains specific secretory (Brunner's) glands . These glands discharge alkaline fluid in the fasting state and are further stimulated by ingestion of food or the administration of exogenous hormones.16 A reliable quantification of normal intestinal secretion is not available and it is here estimated as 1 liter daily. The total daily input to the gut amounts to 9 liters of essentially isotonic fluid. To this must be added variable quantities of fat, carbohydrate, and protein from the diet, protein in digestive secretions, and an unpredictable contribution by desquamated epithelial cells. Finally, electrolytes and water are secreted into the lumen of the bowel, presumably by transepithelial movement, even in areas devoid of specific secretory glands. 17 Multilumen intestinal tubes, combined with the use of nonabsorbable volume markers, have been used to follow the digestion and absorption of test meals and to quantify the progression of chyme through the intestine. Borgstrom et a!. 18 demonstrated dilution of a test meal in the proximal jejunum; later, Fordtran and Locklear 19 estimated the volume of a single, mixed meal in the duodenum (1500 ml), jejunum (750 ml) , and ileum (250 ml). Flow rates of fasting intestinal content have been quantified in the mid and distal small bowel, 20 -23 as well as the effect of feeding on volumes recoverable from these sites. By these techniques, mean fasting volumes in the duodenum of 2.0 ml per min, 24 · 25 in the jejunum of 2.2 ml per min 20 · 21 and of 0.6 ml per min in the ileum 20 · 22 have been calculated. Intestinal volumes increase after meals 21· 23 at times quite sharply. 23 Combining the results of several investigations, a profile of t1uid volumes a long the digestive tract can be constructed (tab le 2) , based on 24 hr and consisting of three meals and an 18-hr period of fasting. Using these figures, the "efficiency" of water reabsorption at different sites can be roughly computed: 45% absorption in the upper small bowel,

TABLE

497

2. Volum e of water in the gut each day

S ite

E x pe rim ental ohservat ion

Cnl c u·

lntccl" volume

Percent age of total

ml

Duodenum

Jejunum Ileum

1500- 2000 ml/mea l ' 9 9000 1500 ml/meal'' 2.0 ml / min fasting" · 2 5 750 ml/meal' 9 5000 2.2 ml/min fasting 2 0 • 2 ' 250 ml/meal' 9 15oo• 0.6 ml/min lasting<~ u. 22 .

Stool

100

55 17

2a

100- 200 ml/day '· '

150

1.7

Approx1mate daily volume; three meals and 18to 21-hr interdigestive period. • Value confirmed experimentally. 23 a

70% absorption in the ileum, and 90% in the colon. However, actual volumes absorbed are greatest in the proximal bowel and decrease aborally (fig. 1) . Two points require further clarification. Well established ileostomies discharge daily volumes of usually less than 1000 ml, 26 · 27 although effluents from recently constructed stomas may be greater. 28 However, intubation studies of the intact bowel suggest a higher volume of fluid in the normal ileum . 23 Information on regional function in the colon is scanty; available data assign a more important role to the proximal colon 29 and suggest that the rectum absorbs water very slowly . 30 · 31 Although fecal water is the major determinant of fecal weight, the physicochemical events by which gut content is finally converted to solid stool are unknown. Water content, which is similar in solid and diarrheal stools, may not be solely responsible for fecal consistency. However, it is apparent that disturbances of water absorption and secretion offer the major clues to the pathophysiology of diarrhea .

Absorption and Secretion in the Int estine Adequate digestion and absorption of dietary macromolecules are essential to norma l intestinal function. The enzymatic and physiochemical events necessary for absorption of fat, carbohydrates, and proteins have been reviewed recently, 32-34and

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further consideration is inappropriate here. However, the consequences of major abnormalities affecting these processes will be discussed. Absorption of electrolytes and water will be summarized, with particular emphasis on osmotic factors, active sodium transport, water absorption, absorption of other electrolytes, and transepithelial secretion into the bowel. Osmolality. The osmolality of meals varies widely 19 ; hypotonic saliva 11 and isotonic gastric secretions 10 modify the ionic strength of gastric contents postprandially. Regardless of intragastric osmolality, meals enter the duodenum where anisotonic chyme stimulates osmoreceptors which are thought to reside in the distal duodenum. 35 By this mechanism, and the presumed intervention of humoral factors , 35 gastric emptying is delayed. Isotonic gastric contents leave the stomach most rapidly; anisotonic meals are retained for longer periods. The process of osmotic equilibrium begins in the stomach 19 and continues in the duodenum.19 Hypotonic meals are rendered isosmotic by movement of water from the lumen and concomitant movement of ions, mainly sodium and chloride into the lumen. Dietary macromolecules are also hydrolyzed to smaller, osmotically active compounds. Water also moves rapidly into the small bowel to dilute hypertonic contents. 36 The rates at which hypertonic fluids are diluted to isotonicity have been compared directly in canine duodenal and ileal segments. 37 The duodenum reduces the osmolality of its contents much faster than does the ileum. The net result of these rapid changes in the chyme is essentially isotonic by the time it reaches the jejunum where most absorption is thought to occur. Subsequently, isotonicity is maintained during distal progression of a meal 19 ; in addition, fasting intestinal contents are isotonic in the distal bowel. 22 · 23 Throughout the intestine, sodium is the major cation of chyme, 19 ' 23 but potassium concentrations increase distally and can be greater than those of sodium in dialysates of feces. 38 Chloride is the major anion of jejunal con-

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tents, 19 but its concentration decreases distally where it is replaced partially by bicarbonate in the ileum 19 ' 23 and organic anions in the colon. 38 Sodium and water absorption. This subject has been extensively reviewed 9 and current views can be summarized as follows . Sodium can be absorbed across intestinal mucosal preparations by an energy-dependent phenomenon ("active transport") that is able to transport sodium from the lumen against gradients of chemical concentration (activity), the negative electrical charge of intestinal mucosa, and in certain circumstances against bulk flow of water. Active transport of sodium may be related to absorption of glucose and certain amino acids. In man, the electrochemical potentials against which sodium is absorbed increase aborally; thus, sodium is absorbed against greater gradients in the distal small bowel. and particularly in the colon. 39· 4° Concomitantly, passive permeability of the bowel to sodium decreased distally. 39 The size of hypothetical, water-filled "mucosal pores" through which sodium and other polar solutes diffuse is thought to decrease in the distal bowel. 39 · 40 Thus, in the ileum and colon a less permeable membrane restricts the passive movement of sodium (and other water-soluble solutes) , but active sodium absorption is more effective. Certain earlier data 41 ' 42 have been interpreted to favor the presence of primary active water transport; however, the mechanism of water absorption is considered currently to be passive, 9 secondary to absorption of solute. A model has been proposed whereby transport of solute (e.g., NaCl) creates an osmotic gradient for water movement. 9 Diamond and Bossert 43 have invoked the development of osmotic gradients in lateral intercellular spaces as the mechanism of water absorption across the mucosa of the gallbladder. As a corollary of the present consensus, water malabsorption is considered as occurring secondary to solute malabsorption, or to the presence of luminal contents that are abnormal, quantitatively or qualitatively .

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Absorption of other electrolytes. Potassium movement across the jejunum and ileum can be explained by passive electrical (potential difference) and chemical concentration gradients. 44 • 45 During balance studies, 23 potassium is absorbed from intestinal contents entering the colon. These findings must be reconciled with the high concentrations of potassium that are found in fecal water, 38 ·potassium secretion into the colon under certain experimental conditions 44 and the common occurrence of potassium depletion in diarrhea. The negative mucosal electrical potential of 20 to 40 mv in the colon 46 • 47 provides a passive force by which potassium can accumulate in the contents until concentrations 2 to 3 times those of plasma are achieved. Moreover, mineralocorticoid secretion may be stimulated by electrolyte losses in diarrhea, thereby increasing the negative colonic potential 47 and augmenting passive losses of potassium. Stools may also contain mucus, desquamated cells and bacteria, all of which could contribute to excretion of potassium. Finally, the water phase of feces may be distributed heterogeneously within solid stools. 38 Compartmentalization of fecal water could explain high local concentrations of potassium in fecal dialysates. 38 Intestinal absorption of anions is more complex. Movements of chloride and bicarbonate are closely coupled, particularly in the distal bowel 48 - 5 0 ; chloride-bicarbonate exchange in the ileum has also been related to sodium and hydrogen ion transport. 5 ° Chloride and bicarbonate can be absorbed together in the jejunum. However, in the ileum and colon, chloride is usually absorbed and bicarbonate is secreted. As chyme passes distally, chloride concentrations decrease and bicarbonate concentrations and the pH rise. Organic anions (acetate, propionate, butyrate, and others) are . 'rominent constituents of stool 5 1• 52 and comprise 70% of fecal anions. Though presumed to result from bacterial conversion of unabsorbed carbohydrate, 51 little is known of their production or fate; one study suggests that these anions (short chain fatty acids)

499

are poorly absorbed from the human colon. 53 Intestinal secretion. Uncertainty as to the precise magnitude and significance of transepithelial intestinal secretions (succus entericus) in health has been emphasized; but under certain pathological conditions, secretion of electrolytes and water is highly relevant to the production of diarrhea. The subject, including cellular origins and biochemical mechanisms of intestinal secretion, has been reviewed recently. 17 Mucosal crypts of Lieberkiihn have been postulated as the site 17 of secretion which has been demonstrated under the following diverse circumstances: (1) Normally in some herbivorous species. Powell et al. 54 observed secretion of electrolytes and water in the guinea pig small bowel. (2) Abnormal physical conditions, such as mechanical bowel obstruction, 55 lowered pH, 5 6 and after irradiation. 5 7 • 5 8 (3) In the presence of chemical stimulants; such as dihydroxy bile acids in the small intestine 59 and colon 60 ; hydroxylated fatty acids, e.g., ricinoleic acid from castor oil and hydroxystearic acid (H. Ammon and S. F. Phillips, unpublished observations); cathartics of the anthraquinone group. 61 (4) In the presence of bacterial toxins; those of Vibrio cholera 62 ; Staphylococcus aureus 6 3 ; Clostridium perfringens 64 ; certain shigellae 65 ; and Escherichia coli. 66 • 67 (5) Stimulation by humoral factors. Mineralocorticoids, which augment sodium absorption and stimulate potassium secretion in the human colon, 68 prostaglandins, 69 gastrin, 7 0 secretin, 70 cholecystokinin, 70 a combination of glucagon and gastrin, 71 and newer polypeptide substances recently isolated from gut mucosa 72 induce secretion in a variety of experimental models. (6) Mucosal disease. Patients with nontropical sprue, 73 intestinal scleroderma, 74 and regional enteritis74· 75 secrete sodium and water into the jejunum. Some bacteria which do not elaborate a recognizable enterotoxin invade the mucosa, produce changes in villus architecture and cause secretion of water. 76 The nature of the fluid secreted in response to these various stimuli remains

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Disorders of Function Causing constant "for a particular region of the Diarrhea bowel 17 ; but fluids accumulating in the proximal and distal bowel . have different Accumulation of new data on intestinal compositions. 17 These differences ·in comfunction permits formulation ofa systemposition are predictable on the basis of atic, although incomplete, classification of specialized transport of electrolytes at difdiarrhea. Although based on the recognizferent sites. It is uncertain if secretion able disorders of ·function, any current arises from a new transport process that scheme cannot categorize all diseases, is initiated by this wide variety of insults, since information is fragmentary in many or whether an existing secretory mechaareas and more than .one mechanism may nism, normally inapparent in healthy pertain to common clinical circumstances. bowel, is stimulated. Alternatively, inhibiThree major categories ·emerge: ( 1) ostion of normal absorption and persistence motic retardation of water absorption ; of a secretory process could be proposed. (2) abnormal electrolyte and water transA recent hypothesis 50 that intestinal port ; (3) disorders of transit. transport of electrolytes reflects the net effect of hydrogen-sodium and chlorideOsmotic Factors bicarbonate exchange has been offered as Overload. Many patients relate diarrhea a basis for secretion in the ileum. In some secretory states, such as that to dietary indiscretions, and physicians frequently ascribe these symptoms to induced experimentally by cholera toxin, "irritable bowel, " yet dietary excess is mucosal structure and glucose absorption poorly documented as a cause for diarare normal. 7. 7 In clinical cholera, oral administration of glucose 78 • 79 and glycine 79 rhea. However, individual and racial variareduces the rate of water secretion. The tions for digestion and absorption of carbohydrate are known and intakes in excess probable mechanism · is that glucose absorption · c~eates osmotic · gradients for of intestinal capacity cause diarrhea. 83 water absorption although a stimulatory Ingestion ofan artificial sweetening agent, effect Of glucose on sodium transport has sorbitol, a nonabsorbable sugar alcohol, also been proposed. 77 ·However, . in sprue has caused diarrhea. 84 Therapeutically, and experimental salmonellosis, the mucodelayed absorption of polyvalent ions (Mg 2 +, P0 4 3 - ) and a nonhydrolyzable, sal structure is abnormal and glucose does not modify the secretory state. 7 3 ' 80 At this nonabsorbable disaccharide (lactulose) time, the nature or existepce of a single is used to evoke catharsis. Some types of or multiple secretory process is unknown diarrhea, for which other causes cannot and the biochemistry of secretion is largely be found, . may occur when the normal unexplored. Increased synthesis of a procompensatory capacity to digest and abtein which stimulates secretion has been sorb is exceeded, under certain dietary suggested. 81 Recently, attention has circumstances. focused on the role of the adenyl cyclaseMalabsorption. Malabsorption · ·of cyclic adenosine monophosphate system carbohydrate, fat, and protein results as an intracellular mediator of secretion, from a wide variety of gastrointestinal particularly in experimental and clinical disease, 32 and diarrhea is a frequent . but cholera. Field's excellent. review 82 should not invariable symptom. The presence be consulted for details. Further, various of certain unabsorbed dietary components hormonal stimuli that induce secretion also in the bowel constitutes an abnormal modify the cyclic adenosine monophos- osmotic load and the relationships between phate system, but it is too early to state malabsorption of foodstuffs and malabthat a common intracellular mechanism is sorption of water warrant further examinaresponsible for all forms of intestinal setion. cretion . Carbohydrate malabsorption occurs in

September 1972

PROGRESS IN GASTROENTEROLOGY

primary disorders of digestion (e.g., lactase deficiency), secondary to mucosal disease of the small bowel (e.g., sprue), 85 and rarely in inherited disorders of monosaccharide transport (e.g., glucose-galactose malabsorption). 86 Lactase deficiency has received most attention and can be considered as a prototype. In this condition, dietary lactose is incompletely hydrolyzed and poorly abfiorbed; barium and test meals are diluted in the small bowel, presumably by osmotic effects generated by nonabsorbable disaccharide. 87 · 88 These events can be reproduced experimentally by the poorly absorbable sugar alcohol, mannitol. 89 Fluid moving into the lumen distends the small bowel and intestinal transit time is reduced. 90 In the colon, disaccharide disappears from the contents 89 and the pH of the colon decreases. Although water is absorbed in the colon, rates of absorption are less than from control or mannitol solutions. 89 An abnormal pH in the colon might impair water absorption and this possibility needs examination. A more attractive hypothesis involves development of additional intraluminal osmotic forces 89 in the large intestine. Bacterial hydrolysis of disaccharides to monosaccharides and subsequent hydrolysis of monosaccharides into even smaller molecules, such as short chain organic acids of 2-4 carbon-chain length, could provide the osmotically active compounds that would retain water in the colon. Indeed anions of short chain organic acids are absorbed poorly by the colon 53 and therefore could act as osmotic cathartics. Their slow transport across colonic mucosa, presumably by nonionic diffusion, is predictable since the pKa is low (approximately 4.8) and pH of the colon usually remains above 5.0 even in the presence of carbohydrate malabsorption. Although the smallest organic anions may be appreciably soluble in water, absorption by aqueous diffusion across the mucosa of the colon may be quite slow since the colon is relatively impermeable to molecules as small as urea. 4° Certain clinical observa-

501

tions are consistent with this hypothesis, e.g., when carbohydrates are fed to children recovering from acute diarrhea, fecal outputs of organic anions increase; however, fecal volumes rise concomitantly resulting in little alteration of anion concentrations.91· 92 Since long chain fatty acids are virtually insoluble in water, even when fully ionized, these compounds which comprise the bulk of fecal fats cannot exert an osmotic effect on water movement. An alternate mechanism for water malabsorption in steatorrhea 6' 7 is necessary. James and co-workers 93 examined steatorrhea! stools by gas liquid chromatography and identified long chain fatty acids, mainly of dietary origin, and also hydroxylated fatty acids. Molecular similarities were recognized between the major fecal hydroxy fatty acid (10 hydroxystearic acid) and a known cathartic, ricinoleic acid (12 hydroxy octadecanoic acid, castor oil). Subsequently, hydroxy fatty acids were demonstrated in normal stools and excess fecal excretion was documented in numerous steatorrhea! diseases, including pancreatic insufficiency. 94 . 96 Intestinal bacteria are able to hydroxylate unsaturated fatty acids of the diet in vitro. 97 This action is assumed to occur in vivo since fecal hydroxy fatty acid excretion can be reduced by antibiotic therapy 98 or removal of long chain fats from diet 99; moreover, considerable metabolism, presumably bacterial, of fats is known to occur in the colon. 100 The relationship between fecal fat excretion and water malabsorption is most readily explicable by altered electrolyte and water transport (see later) . Malabsorption of protein is an infrequent cause of diarrhea. A rare congenital deficiency of the mucosal enzyme, enterokinase, results in incomplete activation of trypsinogen and leads to protein maldigestion, malabsorption, and diarrhea. 101 In the congenital abnormalities of amino acid transport, Hartnup disease, "blue diaper syndrome," and methionine malabsorption, intestinal absorption of amino acids is reduced. 34 Diarrhea is not a feature of

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PROGRESS IN GASTROENTEROLOGY

these diseases, although jejunal malabsorption of water, presumably on an osmotic basis, can be demonstrated 10 2 by a technique similar to that used for the radiological diagnosis of lactase deficiency. 87 Metabolism of unabsorbed amino acids by fecal flora is recognized 34 ' 103 but is not thought to produce diarrhea, with the possible exception of methionine malabsorption. In the one example of this condition, diarrhea was prominent and large amounts of hydroxybutyrate, postulated to be a bacterial byproduct of un absorbed methionine, were excreted m the stools. 103

Abnormal Electrolyte and Water Transport Although stimulation of intestinal secretion exemplifies altered electrolyte and water transport most dramatically, consideration of normal physiological events suggests that even modest impairment of reabsorption in one area, if not compensated for by increased absorption in another area, can lead to diarrhea. Numerous toxic, chemical, humoral, and mucosal factors known to cause diarrhea have been shown to modify water reabsorption, but a complete evaluation of diarrheal disease is not yet available. Bacterial diarrhea. Dysenteric diseases continue as a major worldwide problem. Those most vulnerable are least prepared with respect to age, associated illness, and standards of social and medical care. The basis for recent exciting advances in this subject was established by the study of cholera and the enterotoxin of V. cholerae which is responsible for diarrhea by stimulation of small bowel secretion. 104 Bacterial enteritides have been subject to recent review 105 in which two separate pathogeneses were proposed for a wide variety of bacterial diarrheas: (1) elaboration of filterable enterotoxins without mucosal damage, (2) mucosal injury by direct penetration. Some organisms appear to combine these properties. In both circumstances, abnormal intestinal secretion of electrolytes is demonstrable. The site of secretion is usually the small

Vol. 63, No.3

bowel, and this region has been studied most extensively in clinical disease 106 · 107 and animal models. 77 · 80 Some bacteria also attack the colon, often with ulceration, 105 but detailed study of colonic water and electrolyte transport is lacking. Toxigenic, enteropathic strains of E. coli have no apparent effect on the colons of human volunteers. 108 In the small bowel affected by cholera and nonspecific dysentery, net sodium and water absorption is decreased or net secretion occurs. 106 · 107 Unidirectional flux measurements have been interpreted as showing increased passive sodium permeability, although this alone cannot account for all findings. An additional blood-to-lumen component has been invoked and another mechanism (e.g., active secretion, increased hydrostatic pressure) has been postulated. Secretion of chloride 109 and bicarbonate110 also occurs. Cholera toxin has been reported to alter 110 and cause no change 111 in trans mucosal potential differences. At this time, direct comparison of results obtained in a variety of systems (man, experimental animals, in vitro and in vivo) should be cautious, and firm conclusions are unjustified. The value of in vitro studies is minimized somewhat by the fact that net fluid secretion cannot be examined in many in vitro preparations, although secretion occurs regularly in vivo. Further purification of toxins 112 and elucidation of biochemical mechanisms of secretion should permit the development of a general hyP,othesis for toxin-induced secretion. Bile acids. Forth et al. 113 first demonstrated in vitro an inhibitory effect of bile acids on water transport; subsequently, utilizing intestinal perfusion in vivo, dihydroxy bile acids have been shown to inhibit water absorption reversibly in the canine colon 60 and to provoke secretion in the human colon 114 without producing morphological damage. This effect is independent of conjugation, is concentration-related and is specific for dihydroxy compounds; cholic acid has no effect. The concentrations of bile acids required to impair absorption are similar to those

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PROGRESS IN GASTROENTEROLOGY

occurring in the stools after ileal resection. 114 Dihydroxy bile acids and their conjugates also provoke secretion in the jejunum of hamsters 59 and man (D. L. Wingate, S. F. Phillips, and A. F. Hofmann, unpublished observations). In the hamster, water secretion induced by unconjugated bile acids is rapidly reversible despite the presence of gross morphological changes in villous structure. Unconjugated bile acids inhibit numerous metabolic functions of intestinal mucosa in vitro, 115 although the relevance of these findings to circumstances in vivo is doubted. 116 The secretory effect of bile acids is not associated with marked changes of unidirectional flux rates, 60 • 114 implying that membrane permeability is not greatly increased. Secretion correlates poorly with bile acid absorption and the secretory response is explained best by an effect at the mucosal surface. 60 • 114 Relationships between bile acids and bacteria may be important (fig. 2). Bacterial hydrolysis of the glycine and taurine conjugates is considered a prerequisite for bacterial dehydroxylation of the steroid moiety. Dehydroxylation of cholic acid (trihydroxy, inactive) yields deoxycholic acid (dihydroxy, active). Conversely, bacterial metabolism of chenodeoxycholic acid (active) yields lithocholic acid which is insoluble under usual circumstances in vivo and, presumably, inactive. Although bile acid effects on the colon have been strongly incriminated in the diarrhea of ileal disease, 117 the role of bile acids in the small bowel is more speculative. However, in states of jejunal bile acid deconjugation, such as bacterial overgrowth, 118 an effect of the unconjugated forms on water transport could contribute to diarrhea. Fatty acids. The association between dietary fats, steatorrhea, and diarrhea, mentioned earlier, should be considered here since fatty acids appear to induce diarrhea by impairment of sodium and water absorption. As a prototypic compound, ricinoleic acid (the active principle of castor oil) can be considered. This hydroxy fatty acid alters intestinal motility, 11 9 increases mucus secretion, 12 0 pro-

503

SUBSTRATE -BACTERIAL ENZYME RELATIONSHIPS IN DIARRHEA SUBSTRATE

COLONIC METABOLISM ~

ACTIVE

COMPOUND ConjugatHd Cholic A cid

1. Ouc o njugation 2 , Dehydroltylatio n

Doo-vchoH c A c ;d

l

PRESUMED ~

Inhibit

W ntur Ab sor p ti o n

Di etnry F:at

Hydro>t ylati o n

Hydrox y Fanv A ci d

Carbohydrates

Hydr o ly s is

Mono • ncchn•;no Org11ni c Ani on

Amino A cids

l

1 Non Ab sor babl e l or"~

FIG. 2. Role of bacterial meta bolism of unabsorbed materials in the pathogenesis of diarrhea.

duces "chemical gastroenteritis," 1 2 1 and also decreases sodium transport in vitro. 1 22 Because of chemical similarities between fecal hydroxy fatty acids and ricinoleic acid (see earlier), the diarrhea seen in fat malabsorption has been postulated to be due to hydroxy fats. Currently, in our laboratory, ricinoleic acid and 10-hydroxy stearic acid have been shown to reduce water absorption in the human jejunum and colon. However, a major dietary fat , oleic acid, appears to possess similar properties. Fecal fat excretion can be increased by dietary overload, 123 although not invariably, 1 24 and large doses of corn oil or olive oil (above 300 g daily) can cause Conversely, subthreshold diarrhea. 12 5 doses of castor oil can be absorbed and metabolized without catharisis. 1 2 6 The interactions are complex. Mechanisms by which fatty acids inhibit water absorption are not defined and factors such as solubility in intestinal content, rates of absorption and len gths of intestine exposed to fatty acids will need clarification. Bile acid malabsorption can produce steatorrhea (and diarrhea) and study of events after ileal resection has been rewarding since, under these circumstances, the effects of bile acid and fat malabsorption can be separated. 127 After resection of the major site of bile acid reabsorption, the colonic mucosa is exposed to greater amounts of dihydroxy bile acids (deoxycholic, chenodeoxycholic); these compounds are present in concentrations that inhibit colonic water reabsorption during perfusion studies: 114 This mechanism has been incriminated in the diarrhea of ileal resection. 117 In certain instances, 1 2 7

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t reatment with cholestyramine or lignin, 128 agents which render bile acids insoluble, lowers the effective concentration of bile acids in the colon, relieves diarrhea, but increases steatorrhea. 99 Other patients, usually those with more severe steatorrhea, have lesser concentrations of bile acids in the aqueous phase of stools but greater amounts of hydroxy and other fatty acids. 99 In these, sequestration of bile acids does not reduce stool weight or frequency, but removal of long chain fats from the diet is efficacious. 99 Humoral and chemical factors. When administered by arterial infusion, prostaglandins provoke secretion of isotonic fluid into the lumen of isolated intestinal loops 69 ; these agents also stimulate mucosal adenyl cyclase. 82 High levels of prostaglandin F2a have been extracted from tumors of patients with diarrhea associated with ganglioneuromas, pancreatic islet cell tumors, ileal carcinoids, and medullary thyroid tumors. 129 Other gastrointestinal hormones, gastrin, secretin, cholecystokinin, and glucagon are also capable of modifying water absorption in man and experimental animals. 70 • 71 • 130 Recently two additional polypeptides named vasoactive intestinal peptide and gastric inhibitory peptide have been isolated from intestinal mucosa and shown to have dramatic effects of intestinal secretion. 72 Hypersecretion of gastric JUlCe is associated with diarrhea in many mstances of the Zollinger-Ellison syndrome. 131 Maldigestion of fat, leading to steatorrhea, is often present and has been extensively studied 132 • 133 ; steatorrhea may contribute to diarrhea under these circumstances. In addition, electrolyte and water absorption in the jejunum may be abnormal in some patients 134 and this abnormality may be related to jejunitis 13 5 or an abnormal pH in the jejunum. 134 • 1 36 Diarrhea is sometimes dramatically relieved by gastric aspiration. Diarrhea may be aggravated by changes in ileal function where an acid pH has been shown to impair vitamin B 12 132 and water 56 absorption.

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But the pathophysiology of gastrin overproduction is even more complex since gastrin may impair mucosal transport of electrolytes and water directly 70 and may also influence intestinal motility. 137 In other cases of pancreatic islet cell tumor, diarrhea occurs without gastric hypersecretion and gastric aspiration does not ameliorate the symptoms. A marked choleresis, hypokalemia, and achlorhydria 1 38 • 139 are observed in this syndrome. Bile f1ow is increased, probably . by concomitant action on the hepatobiliary system of a humoral agent such as secretin. 138 • 14 ° Further study of these metabolically active tumors should be revealing. Thus, overproduction of normal hormones or synthesis of abnormal, active peptides by tumor cells has profound effects on many aspects of digestive function, including the stimulation of intestinal secretion. Moreover, it is possible that these humoral agents and exogenous chemical stimuli (e.g., bacterial enterotoxins) may act on the enterocyte via a single, intracellular mediator involving cyclic adenosine monophosphate · and adenyl cyclase. 82 . Other chemical agents that modify water transport include certain absorbable cathartics, 61 some diuretics, 141 and antidiuretic hormone . 142 Misc ellaneous diseases. In the rare . congenital abnormality, chloridorrhea, 143 • 144 excess chloride is secreted in the stool, leading to severe metabolic disturbances. A disturbance of ileal exchange between chloride and bicarbonate has been proposed to account for the abnormality. 145 Villous and other tumors of the colon 146 • 147 may secrete or exude mucus which is a complex mixture of mucopolysaccharides in an isotonic electrolyte solution, rich in potassium. 147 • 148 Segments of colon containing villous tumors secrete sodium, potassium, and water. 149 The composition of mucus from villous adenomas and from the normal colon is similar (S. F. Phillips, unpublished observations); moreover, electrolytes are readily dialyzable from mucus in vitro 148

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and it has been postulated that the colon in vivo normally reabsorbs the electrolytes contained in mucus. 148 Ulcerative, inf1ammatory, neoplastic, and allergic 150· 151 conditions may exude protein, blood, or mucus into the bowel. Electrolyte and water transport may be altered in inflammatory bowel disease152-154 and this abnormality can be corrected by steroid treatment.75 Although exudation is an uncommon single cause of diarrhea, in some instances of colitis, frequent bowel movements may be due to a "pseudodiarrhea"; i.e., evacuations consist largely of exudate and blood whereas stasis of solid fecal matter is demonstrable in the proximal colon . 155 · 156 Diffuse mucosal disease, such as nontropical sprue, leads to gross abnormalities of electrolyte, water, and glucose absorption. Indeed, secretion of sodium and water into the jejunum is prominent 73 and abnormalities of mucosal permeability have been reported. 157 Disorders of Transit

For absorption to proceed normally, chyme must be mixed and digested adequately arid exposed to adequate mucosal surface for a critical minimum time. The processes of digestion and absorption are being progressively elucidated; however, mixing and propulsive factors are less completely defined. Interrelationships are intuitivelY apparent but poorly documented . . Mucosal factors. Evidence is accumulating that the bowel remaining after resection is capable of considerable compensatory hypertrophy of function 158 · 159 and even of : structure, 159 · 160 particularly if normal . nutrition can be maintained. 161 Survival and normal development, despite life-long diarrhea, have been reported after preservation of only a few centimeters of proximal small bowel. 159 · 162 Fecal water losses after resections can be complicated by additional factors such as bile acid effects on the colon, steatorrhea, gastric hypersecretion, and changes in bacterial flora. 105 In certain circumstances,

505

the ability to delay intestinal transit by mechanical or pharmacological means can be used to facilitate absorption in the remaining bowel. Attempts to slow transit by antiperistaltic segments have achieved qualified success . 163 - 165 Motor fa ctors : hypomotility. Normal intestinal motor activity is an important determinant of the relative sterility of the small bowel. 166 The consequences of hypomotility and stasis whether due to strictures, diverticula, blind loops, or neuromuscular disease relate to bacterial overgrowth in the small bowel. 105 Steatorrhea is often present and is thought to result from bacterial deconjugation of bile acids, rapid absorption of free bile acids by nonionic diffusion, and jejunal bile acid deficiency. 118 The importance of abnormal villous architecture in the small bowel adjacent to bacterial colonies is uncertain . 116 · 167 Diarrhea has been related to excess of fat in the lumen of the small bowel and colon, possibly mediated by hydroxy fatty acids . 98 An inhibitory action of free bile acids on jejunal water absorption 59 and changes in jejunal morphology produced by unconjugated bile ac ids could also contribute. 59 · 168 Hypermotility . An association between rapid intestinal transit and malabsorption is appealing, yet experimental data to support this concept are meager. 169 When rapid transit and malabsorption coexist, the cause-effect relationships are poorly defined. Thus, increased volumes in the lumen, due to incomplete absorption, may accelerate transit as in perfusion studies. 90 · 170 Moreover, several factors cited earlier as modifying intestinal water transport, fatty acids, bile acids, and humoral agents, also have effects on intestinal smooth muscle function. The relationships among volume, flow rates, and water malabsorption have been tested experimentally and termed "volumogenic diarrhea. " 171 With greater rates of infusion into the duodenum , total fluid absorption increases; however, the proportion of the infusion solution that is absorbed decreases and the absolute volume required

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to produce diarrhea decreases. Fluid loss from the rectum can be modified by the hydrodynamic restrictions on flow imposed by the ileocecal valve and the anal sphincter. 172 Hormonal and pharmacological stimuli of intestinal smooth muscle have been incriminated in certain types of diarrhea.173 Prostaglandins stimulate intestinal smooth muscle in vitro, 174 decrease transit time, cause diarrhea in volunteers, 175 and have been implicated clinically in diarrhea. 129 Other pharmacologically active agents (secretin, pancreozymin, gastrin, and 5-hydroxy tryptamine) stimulate intestinal smooth muscle 17 3 and are secreted by certain tumors that may produce diarrhea. However, relationships among intest.inal smooth muscle activity, propulsion of contents, and absorption are extremely complex. Connell 176 has emphasized that decreased muscular function in the colon may be associated with diarrhea, and augmented muscular · activity may be associated with constipation. Clinical Correlations Infectious diarrhea . Gorbach 17 7 summarized recent experimental studies of the bacterial dysenteries and proposed that acute bacterial diarrhea can be considered as a "toxin disease." Acute viral infections are less readily documented; in fact, the frequency of a viral etiology for nonspecific diarrhea is uncertain. 178· 179 Little is known of pathophysiological changes induced by viral infection. In a model of transmissible viral gastroenteritis in pigs, the onset of watery diarrhea coincides with atrophic changes in villous architecture, similar to those in sprue. 180 Acute infectious diarrhea occasionally produces transient steatorrhea 181 and disaccharide deficiency 182 which could represent additional pathophysiological mechanisms. The diarrhea of parasitic infestations is poorly defined. Mucosal changes may occur 183 and these can be associated with steatorrhea. Exudation of plasma proteins

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has been reported .in, capilla~iasis, 184 and changes in the bacterial flor~'; ~f the gut have been implicated 18 ~ in the diarrhea · of some infections. ·' ·· ·· · Iatrogenic. Use and abuse ' o( drugs constitute a frequent cause of diarrhea. Laxative agents include nonabsorbable ionic cathartics and hydroxy fatty acids (ricinoleic acid, castor oil) . The important anthraquinone laxatives cause . ~ecretion in the small bowel ·and colon of animal models. 61 · 186 These ' drugs also undergo enterohepatic circulation. The · unconjugated forms are absorbed in the small bowel and conjugated in the liver with glucuronic acid, and possibly other anions and conjugates are secreted in bile. 186 Conjugation impairs absorption from the small bowel allowing the drug to reach the colon where impaired sodium and water reabsorption 61 is proposed as the cause of catharsis. Chronic abuse of such laxatives can result in protein-losing gastroenteropathy, . steatorrhea, . electrolyte depletion, and secondary hyperaldosteronism. 187 • 188 . · Gastrointestinal resections . .· Gastroduodenal surgery results in maldigestion and malabsorption bf fat in up to_: pO% of patients 189 and relevant mechanisms of . steatorrhea have beeri reviewed. 190: When steatorrhea is present, . water malabsorption may result from mechanisms .already discussed. After gastroenterostomy, the small bowel can be the site of ·bacterial overgrowth, thereby functioning as a blind loop. 191 · 192 Other possible factors · contributing to diarrhea include rapid intestinal transit, 173 attributed to postoperative "dumping" and emergence of latent lactose malabsorption. 193 · _ Resection of the small bowel lias . been discussed above. Factors of variable importance in individual examples: include length and functional status of re'm aining bowel, intestinal stasis with bacterial overgrowth, and the site of resection.·1n this context, loss of the ileum is of particular importance since ileal resection depletes the bile acid pool, thereby aggravating any existing steatorrhea due to decreased

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absorptive surface. 189 In addition, passage of excess bile acids into the colon may induce water malabsorption there. Ileostomy represents a special case of intestinal resection, but one in which the continued loss of excess water and sodium from the gut can be examined for long term complications. The pathophysiological sequelae of ileostomy include increased susceptibility to sodium depletion dehydration, oliguria, and renal calculi. Such events are predictable from present concepts of intestinal and renal function and have been discussed previously in this context.194 Recently, interruption of the enterohepatic circulation of bile acids has been proposed as a causative factor in the increased incidence of cholelithiasis afterileal resection. 195 Partial resection of the colon is commonly performed but has received little attention. Length of residual large bowel is probably important, since stools from proximal colostomies are more liquid than those from distal stomas. 196 However, when resection and il!}astomosis are performed, the anatomi· c~l · consequences may differ; proximal colectomy is often accompanied by resection ofthe terminal iieum. Based on present knowledge, removal of the proximal colon should impair water absorption to a greater degree than more distal resections. · . \fagal section. Postvagotomy diarrhea is occasionally a troublesome complication of vagal section. Ignorance of the true incidertce and an abundance of uncontrolled obser~ations have raised unwarranted fear of the procedure. 197 Williams and Cox 197 estimate the incidence as 20%, the vast ma]ority of which are transient or episodic. They '. feel that the associated gastric "drainage procedure" is unimportant, tnat · a close relationship has not been est~blished between steatorrhea and diarrhea, and that the pathogenesis of diarrhea is uncertain. Selective vagotomy is associated with a lower incidence of diarrhea; thus, extragastric effects of vagal denervation may be important. Alteration of intestinal motility, bacterial

507

overgrowth, impairment of pancreatic function, 198 and lactase deficiency 193 have also been incriminated. Electrolyte and water absorption in the vagally denervated intestine has not been reported and warrants investigation. Fortunately, the course is often intermittent and, in the majority, the ultimate prognosis is good. Structural disease of the small and large intestine. Despite the advances in understanding of normal and abnormal intestinal function already discussed, few diseases have been studied in sufficient depth by techniques that permit an evaluation of pertinent mechanisms. With small intestinal disease, malabsorption of fat, carbohydrate or bile acids may be complicated by impaired water absorption in the proximal intestine. 74 • 75 If the colon is normal, compensation by the large bowel estimated to be 2500 ml water per day 199 should overcome the proximal defects. Nontropical sprue is an example of the multiple ramifications resulting from failure of small intestinal function. Brush border digestive failure, 85 impaired cholecystokinin-pancreozymin release with secondary pancreatic insufficiency 200 and micelle formation, 201 intestinal secretion, 73 and exudation 202 may all contribute to water malabsorption in the jejunum, by mechanisms discussed above. In one example of sprue, 23 more than 3000 ml of water entered the colon daily and diarrhea, with daily fecal weights of 300 to 500 g, was severe. Several questions arise. Was reserve function of the colon exceeded? How was colonic function influenced by unabsorbed carbohydrate and fats which were in the contents? Granulomatous and ulcerative colitis reduce electrolyte and water absorption in the colon, 152 ' 153 but secretion is not usual. The efficiency of normal colonic water absorption (90% or more) and the relatively small increase in stool water required to produce diarrhea (100 to 200 ml per day) imply that subtle changes in colonic function could cause significant symptoms. In ulcerative colitis, changes in the histology 203 and disaccharidase

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activity 204 of the small bowel have been reported although their clinical significance is uncertain. Metabolic diseases . Juvenile diabetics with neuropathy may suffer intermittent bouts of diarrhea without apparent cause. Although numerous mechanisms have been postulated, the studies of Whalen et a!. 205 "failed to demonstrate consistent abnormalities of jejunal morphology, pancreatic function, fat absorption, intestinal flora, and water and electrolytt' absorption during perfusion studies. Nevertheless, test meals were diluted abnormally in the ileum and transit through the distal small bowel was delayed. Studies of autonomic innervation suggested interruption of afferent pathways, although efferent mechanisms, as judged by response to pharmacological agents, were normal. Specific syndromes of diarrhea in primary endocrine dysfunction are poorly defined. Untreated Addison 's disease may cause impaired fat absorption 206 and mineralocorticoids promote potassium loss from the colon. 207 Hypothyroidism reduces and hyperthyroidism increases the frequency of bowel movements. 208 Hyperthyroidism increases the frequency of the "pacemaker potentials" which govern muscular activity in the small boweF 09 ; the relationship of this finding to transit, absorption, or diarrhea has not been examined. Functional diarrhea; irritable bowel syndrome. Elucidation of each new facet of gastrointestinal function has raised hopes that a pathogenesis for "functional diarrhea " was imminent. Disorders of colonic motor function, 210 disaccharide digestion, 211 and prostaglandin metabolism 175 are recent contenders for this dubious honor. Pathophysiological data on the nature of the syndrome are few. The symptoms are chronic, sometimes intermittent, aggravated by stress, and unrelated to known structural disease of the gut. 212 • 213 In one study, excess fecal water was documented. 5 Many fundamental questions are unexplored. Is increased fecal frequency invariably associated with water malabsorption? Steatorrhea

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precludes the diagnosis, but is fecal excretion of bile acids, hydroxy fatty acids, organic anions, sodium, and other electrolytes increased? Is the fecal flora abnormal?

Investigation of Diarrhea Stool analysis. Standard clinical, laboratory, and radiological examinations will not be considered; rather, stool composition will be reviewed and findings relevant to pathogenetic factors will be emphasized. Fecal composition has been documented in health and normal values for daily excretion of water, solids, fat, nitrogenous matter, and inorganic materials have been established. 2 14 Although day to day and individual to individual variations are marked, mean values from most authors are surprisingly constant. For instance, mean fecal weight was 115 and 126 g per day in two series of control subjects 5 • 6 ; in 108 normal subjects reviewed at our institution, the figure was 120 g per day (A. F. Hofmann; unpublished observations). These studies did not employ fecal markers such as chromic oxide; thus, individual values may reflect variability of defecation rather than variations in the amounts arriving at the rectum. In health, fecal water is 60 to 85%5 of total stool weight or 70 to 130 ml per day; diarrhea is usually present when stool weight exceeds 200 g per day, 7 of which 60 to 95% (approximately 200 ml) is water. · Daily fecal weights may provide some clues as to the cause of diarrhea. With "functional bowel disease" fecal weights are increased slightly (mean 218 g per day) but less than in pancreatitis (300 to 400 g per day) and untreated sprue (515 g per day). 5 • 215 Fecal losses of greater than 1000 g per day occur when osmotic diarrhea is produced experimentally by mannitol, 216 in bile acid diarrhea 127 • 216 and in cholera. 10 ' Villous adenomas and watery diarrhea due to islet cell tumors can produce stools in excess of 1000 g per day. Colonic disease is often characterized by frequent small stools. Fecal cations are predominantly potas-

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sium, sodium, magnesium, and calcium (fig. 3). In many diseases sodium is the major cation, in concentrations of up to 100 mEq per liter, and sodium excretion increases directly with the stool volume. 8 Predominance of potassium in concentrations above 100 mEq suggests excess secretion of mucus as in villous adenoma. The major anionic component is organic; acetate, propionate, butyrate, and lactate predominate. 51 ' 52 Fecal weight and fecal organic anion excretion are closely correlated suggesting that excretion of organic anions influences bowel habit. 52 · 217 Changes in the diet and use of broad spectrum antibiotics do not greatly alter concentrations of organic anions in fecal dialysates, 51 although carbohydrate feeding increases total output of these ions. 52 If organic anions arise only from bacterial metabolism of dietary carbohydrate, such manipulations might be predicted to influence fecal anions to a greater degree. Participation of other substrates, possibly of endogenous origin, in production of organic anions is unknown. Other anions may comprise the major losses in certain diseases. In cholera, bicarbonate is excreted in concentrations greater than those of plasma, leading to hypokalemic acidosis. 104 Organic anion components of cholera stools have not been reported. Excretion of chloride as the major fecal anion occurs in chloridorrhea. Although the rare congenital form of this disease has been studied most intently, a secondary form resulting from the metabolic disturbances of diarrhea has been postulated.218 Fecal fat excretion can be influenced by diet, but an endogenous component exists; limits in health and firm criteria for a diagnosis of steatorrhea are well defined. Less attention has been directed to qualitative aspects of stool lipids. Incrimination of certain fatty acids in the pathogenesis of water malabsorption has prompted the qualitative analysis of stool lipids. 93 · 94 Fecal excretion of labeled bile acids 219 and bile acid turnovers 220 can be used to assess bile acid malabsorption . The methodology of qualitative stool

Chloride

Phosphate Sulfate

200 Bicarbonate Calcium

150

Magnesium Ammonium

Other organic anions

Sodium Lactate Butyrate Proprionate

50 Potassium

Acetate

FIG. 3. Ionic composition of stool water, modified from Wrong et a!. 38 and Fernandez et a!. 52

analysis and of bile acid kinetics currently restricts such analyses to specialized laboratories and the significance of these studies needs further evaluation. If clinical importance can be demonstrated, simpler diagnostic approaches will be necessary before general use will be possible. Carbohydrate malabsorption may result in fecal excretion of sugars which can be detected by standard tests. Bacterial metabolism of carbohydrates reduces pH in the colon; this can be examined by simple techniques together with the presence of organic anions in stools. 52 A promising new approach to metabolism of unabsorbed materials by fecal flora is the excretion of 14 C0 2 in breath. The technique has been applied to lactose malabsorption221 and also to metabolism of bile acids labeled with 14 C glycine. 222 · 223 The fate of labeled bile acids can be used to diagnose states of bacterial overgrowth in the small intestine, 222 · 22 3and when combined with excretion of 14 C in stools 223 offers a simple simultaneous test for bile acid malabsorption. In summary, quantification of fecal solutes, including the presence of unabsorbed dietary components, can be

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510

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disease, 127 despite an increase in the severity of steatorrhea, caused by further FECAL SOLUTE depletion of the bile acid pool from inCNOUU toWil BOWEl S£Cllfli0N .. ., SODIUM creased loss in the stools. As yet, treatSt!A!OU~r• -COI.OHICSECRniON ,............ - - ........... ment of steatorrhea due to bile acid de~ALUSOIII"TION (8!I(U!dS, 0H · Iatty ~cids) ~ ficiency by adequate replacements is ------- [ ElUDAJIOPI·--------- POTASSIUN'I ~ MUCUS unavailable without unacceptable catharCHLORIDE ____..., WATER tic side effects. Cholestyramine has not COlONIC OVfRPIWOUCTIONAN D.. _oRGANIC~NION~/ proven an effective treatment for non=~.:IIA~CC:~7r11Cl ·---M.UABSORPTION [ SMAll BOWEl MAUBSOIIPTION- SUGARS specific diarrhea in the tropics. 225 SAUN£ lAXATIVES·------- = T IONS Abnormal intestinal secretion can be reduced by the use of oral glucose. This FIG. 4. Proposed scheme by which malabsorption measure is traditional treatment for of water and solute can be related to mechanisms of infantile diarrhea and also has a rational diarrhea in certain diseases. basis for the treatment of cholera 78 • 79 • 226 used to speculate on the genesis of diar- since, in experimental cholera, secretion is rheal fluids (fig. 4). reduced by glucose. 77 In cholera, glucose absorption which is normal is thought Therapeutic Considerations to establish an osmotic gradient which can augment water absorption. A similar Specific therapy of any underlying disease and more common symptomatic mea- technique has proved successful in the sures will not be considered; rather, some author's hands for the treatment of paapplications of newer pathophysiological tients with extensive intestinal resection. concepts to the treatment of certain syn- A flavored, isotonic, electrolyte-glucose dromes will be reviewed. solution can be prepared by the patient, In the presence of gross steatorrhea, at little cost, and taken regularly as a diarrhea can be ameliorated by reduction supplement. of long chain fats in the diet. 99 • 127 ExperiGastric hypersecretion should be mentally, broad spectrum antibiotics suspected when intractable diarrhea and have also been effective. 98 Reduction of electrolyte depletion, sometimes presentdietary fat may require, for maintenance ing as hypochloremic alkalosis, comof adequate nutrition, the substitution by plicate small bowel resection. 227 - 2 30 A medium chain triglycerides . The theradesire to avoid additional gastric surgery peutic role of medium chain triglycerides may prompt treatment with large doses has been reviewed 224 and is founded largely of anticholinergics or gastric radiation. on the caloric values of such supplements. In some instances, gastric resection or Reduction of dietary disaccharides is vagotomy and pyloroplasty have been conventional and effective treatment for effective in reducing diarrhea. primary disaccharidase deficiencies. The When intestinal failure is complete, incidence and importance of carbohydrate hyperalimentation offers the only available intolerance secondary to other diseases support while the results of more definitive is uncertain; reduction of lactose intake therapy are awaited. The subject has been can be beneficial in infectious diarrhea, reviewed extensively. 231 • 232 after gastric surgery, and in inflammatory Concluding Remarks diseases of the bowel. Bile acid diarrhea can be treated with Diarrhea is an historic and ubiquitous agents that bind bile acids and remove expression of digestive-absorptive failure. them from solution (i.e., cholestyramine As the normal processes of gut function 4 g four times per day) and when facilities have been clarified, insieht has been for study of bile acid kinetics are not gained into the pathogenesis of water available, a therapeutic trial is justified. malabsorption; but our appreciation of This treatment has been effective in ileal normal and abnormal processes is still A CLASSIFICATION OF THE PATHOGENESIS OF DIARRHEA IN MAN

C I.INICAL EXAMPLE

PATHOGENESIS

OISIWCIIOII•••·-SM.Ul

• ~(liiiii OUL !JC!SS

").

Ill! ACiti ...........

INfL UIIIATOn u o ~T OPl ASIIC OISUSIS

CIHJIIIOI)IIRII!A .................... -

tNCAEASEO FECAL

SECRETION .......... -

CHLORIDE MALABSORPTION · · -

A•.o.clUIA

September 1972

PROGRESS IN GASTROENTEROLOGY

imperfect. The conceptual framework of a current classification is proposed with the realization that some separations are artificial, much is speculative and further experimental examination is required. The role of the intestinal flora in these proposals needs emphasis. Specific bacterial enterotoxins appeal as likely explanations for many infectious diarrheas. In addition, interactions between fecal flora and unabsorbed dietary components may be important links between malassimilation of the diet and malabsorption of water. The speculation that some of the mechanisms reviewed here may explain functional bowel disorders is intriguing and deserving of further study. REFERENCES 1. Cunnick WR, Eide KA, Smith NJ: Digestive disease as a national problem. IV. Disability claim study of digestive disease. Gastroenterology 54:246-252, 1968 2. Sheehy TW: Digestive disease as a national problem. VI. Enteric disease among United States troops in Vietnam. Gastroenterology 55: 105-112, 1968 3. Connell AM, Helten C, Irvine G, eta!: Variation of bowel habit in two population samples. Br Med J 2:1095-1099, 1965 4. Wollaeger EE, Comfort MW, Weir JW, et a!: The total solids, fat and nitrogen in the feces. Gastroenterology 6:83-92, 1946 5. Pimparkar BD, Tulsky EG, Kaiser MH, et a!: Correlation of radioactive and chemical fecal fat determinations in the malabsorption syndrome. I. Studies in normal man and functional disorders of the gastrointestinal tract. Am J Med 31:910- 926, 1961 6. Skala I, Krondl A, Vulterinova M, et al: Composition of feces in steatorrhea of different etiology: Mutual relationship between volume of feces, water, dry matter, nitrogen and fat content. Am J Dig Dis 13:204-212, 1968 7. Raffensberger EC, D'Agostino F, Manfredo H, et a!: Fecal fat excretion, an analysis of four years experience. Arch Intern Med 119:573576, 1967 8. Fordtran JS, Dietschy J: Water and electrolyte movement in the intestine. Gastroenterology 50: 263-285, 1966 9. Schultz SG, Curran PF: Intestinal absorption of sodium, chloride and water. Handbook of Physiology, sect 6, Alimentary Canal, vol 3. Edited by CF Code, W Heidel. Washington

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DC, American Physiological Society, 1968, p 1245- 1275 10. Davenport HW: Physiology of the Digestive Tract. Second edition. Chicago, Year Book Medical Publishers, 1966 11. Thaysen JH, Thorn MA, Schwartz IL: Excretion of sodium, potassium, chloride and carhondioxide in human parot id saliva. Am J Physiol 178:155-159, 1954 12. Rune SJ: Gastric acid secretion after the ingestion of solid food. Scand J Gastroenterol 3(suppl1):11-61, 1968 13. Doubilet H, Fishman L: Human biliary-pancreatic secretion. Am J Gastroenterol 35:499512, 1961 14. Lockwood JS, Randall GT: The place of electrolyte studies in surgical patients. Bull New York Acad Med 25:228-235, 1949 15. DeBeer EJ, Johnston CG, Wilson DW: The composition of intestinal secretions. J Bioi Chern 108:113-120, 1935 16. Stening GF, Grossman MI: Hormonal control of Brunner's glands. Gastroenterology 56:10471052, 1969 17. Hendrix TR, Bayless TM: Intestinal secretion. Ann Rev Physiol37:139- 164, 1970 18. Borgstrom B, Dahlqvist A, Lundh G, et a!: Studies of intestinal digestion and absorption in the human. J Clin Invest 36:1521-1536, 1957 19. Fordtran JS, Locklear TW: Ionic constituents and osmolality of gastric and small intestinal fluids after eating. Am J Dig Dis 11:503-521, 1966 20. Whalen GE, Harris JA, Geenen JE, et a!: Sodium and water absorption from the human small intestine. Gastroenterology 51:975-984, 1966 21. Soergel KH, Hebert RJ: Post cibal changes of small intestinal contents in man (abstr). Gastroenterology 58:1051, 1970 22. Devroede GJ, Phillips SF: Studies of the perfusion technique for colonic absorption. Gastroenterology 56:92-100, 1969 23. Giller J, Phillips SF: Colonic absorption of electrolytes and water in man: A comparison of 24 hour ileal content and feces (abstr). Gastroenterology 58:951, 1970 24. Phillips SF, Summerskill WHJ: Occlusion of the jejunum for intestinal perfusion in man . Mayo Clin Proc 41:224-231, 1966 25. Modigliani R, Bernier JJA: Absorption of water, sodium and glucose in the human jejunum, studied with an occluding balloon at variable flow rates. Gut 12:184-193, 1971 26. Kanaghinis T , Lubran M, Coghill NF: The composition of ileostomy fluid. Gut 4:322-338, 1963 27. Kramer P : The effect of varying sodium loads

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on ileal excreta of human ileostomized subjects. J Clin Invest 45:1710- 1718, 1966 28. LeVeen HH, Lyons A, Becker E: Physiologic adaptation to ileostomy. Am J Surg 103:35- 41, 1962 29. Devroede GJ, Phillips SF, Code CF, et al : Regional differences in rate of sodium and water insorption from the human large intestine. Can J Physiol Pharmacol49:1023-1029, 1971 30. Devroede GJ, Phillips SF: Failure of the human rectum to absorb electrolytes and water. Gut 11:438- 442, 1970 31. Edmonds CH: Absorption of sodium and water by human rectum measured by a dialysis method. Gut 12:356-362, 1971 32. Jeffries GH, Weser E, Sleisenger MH: Malabsorption. Gastroenterology 56:777-797, 1969 33 . Gray GM : Carbohydrate digestion and absorption. Gastroenterology 58:96-107, 1970 34. Saunders SJ, Isselbacher KJ: Intestinal absorption of amino acids. Gastroenterology 50: 586- 595, 1966 35. Hunt JN, McDonald I, Spurrell WR: The gastric response to pectin meals of high osmotic pressure. J Physiol (Lond) 115:185- 195, 1951 36. Fordtran JS, Rector FC, Ewton MF, et a! : Permeability characteristics of the human small intestine. J Clin Invest 44:1935- 1944, 1965 37. Hindle W, Code CF: Some differences between duodenal and ileal sorption. Am J Physiol 203: 215-220, 1962 38. Wrong 0, Metcalfe-Gibson A, Morrison RBI, et a!: In vivo dialysis of feces as a method of stool analysis. Clin Sci 28:357-375, 1965 39. Fordtran JS, Rector FC Jr, Carter NW : The mechanisms of sodium absorption in the human small intestine. J Clin Invest 47:884-900, 1968 40. Billich CO, Levitan R: Effects of sodium concentration and osmolality on water and electrolyte absorption from the intact human colon. J Clin Invest 48:1136- 1347, 1969 41. Parsons DS, Wingate DL: The effect of osmotic gradients on fluid transfer across rat intestine in vitro. Biochem Biophys Acta 46 :170-183, 1961 42. Grim E : Water and electrolyte flux rates in the duodenum, jejunum, ileum and colon, and effects of osmolality. Am J Dig Dis 7:17- 27, 1962 43. Diamond JM, Bossert WH: Standing gradient osmotic flow . J Gen Physiol 50:2061- 2083, 1967 44. Phillips SF, Code CF: Absorption of potassium in the small and large intestine. Am J Physiol 211 :607- 613, 1966 45. Phillips SF, Summerskill WHJ: Water and electrolyte transport during maintenance of isotonicity in human jejunum and ileum. J Lab Clin Med 70:686- 698, 1967 46. Geall MG, Spencer RJ, Phillips SF: Trans-

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mural electrical potential difference of the human colon. Gut 10:921-923, 1969 47. Edmonds CJ, Godfrey RC: Measurement of electrical potentials of the human rectum and pelvic colon in normal and aldosterone treated patients. Gut 11 :330-337, 1970 48. Devroede GJ, Phillips SF: Conservation of sodium, chloride and water by the human colon. Gastroenterology 56:101-109, 1969 49. Turnberg LA, Fordtran JS, Carter NW, et al: Mechanism of bicarbonate absorption and its relationship to sodium transport in the human jejunum. J Clin Invest 49:548-556, 1970 50. Turnberg LA, Bieberdorf FA, Morawski SG, et al: Interrelationships of chloride, bicarbon· ate, sodium and hydrogen transport in the human ileum. J Clin Invest 49:557-567, 1970 51. Rubinstein R, Howard AV, Wrong OM: In vivo dialysis of feces as a method of stool analysis. IV. The organic anion component. Clin Sci 37:549- 564, 1969 52. Fernandez LB, Gonzalez E, Marzi A, et a! : Fecal acidorrhea. N Eng! J Med 284:295-298, 1971 53. Dawson AM, Holdsworth CD, Webb J: Absorption of short chain fatty acids in man. Proc Soc Exp Bioi Med 117:97- 100, 1964 54. Powell DW, Malawer SJ, Plotkin GR: Secretion of electrolytes and water by the guinea pig small intestine in vivo. Am J Physiol 215:12261233, 1968 55. Shields R: Surgical aspects of the absorption of water and electrolytes by the intestine. Monograph Surg Sci 1:119-172, 1964 56. Hochman R, Kottmeier PK, Adamsons R, et a! : Effect of gastric juice on the absorption of water and chloride in the ileum. Am J Surg 119:64- 66, 1970 57. Curran PF, Webster EW, Hovsepian JA : The effect of x-irradiation on sodium and water transport in rat ileum. Radiat Res 13:369-380, 1960 58. Sullivan MF: Sodium, water and B 12 absorp· tion in irradiated rats: influence of bile, Gastrointestinal Radiation Injury. Edited by MF Sullivan. Excerpta Medica Foundation, Reidel, Dordrecht, Netherlands, 1968, p 216-227 59. Teem MV, Phillips SF: Perfusion of the hamster jejunum with conjugated and unconjugated bile acids: Inhibition of water absorption and effects on morphology. Gastroenterology 62: 261-267, 1972 60. Mekhjian HS, Phillips SF: Perfusion of the canine colon with unconjugated bile acids. Ef· feet on water and electrolyte transport, mor· phology and bile acid absorption . Gastroenterology 59:120- 129, 1970 61. Forth W, Rummel W, Baldauf J : Wasser- und

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Electrolytbewegung am Dunnund Dickdarm unter dem Einfluss von Laxantion, ein Beitrag zur Klarung ihres Werkungmechanismus. .Naunyn Schmiedebergs Arch Pharmakol Exp Pathol 254:18-32, 1966 62. Greenough WB III, Carpenter CCJ, Bayless TM, et a! : The role of cholera exotoxin in the study of intestinal water and electrolyte transport, Progress in Gastroenterology. Edited by GBJ Glass. New York, Grune and Stratton, 1970 63. Sullivan R, Asano T: Effects of staphylococcal enterotoxin B on intestinal transport in the rat. Am J Physiol 220:1793-1797, 1971 64. Strong DH, Duncan CL, Perna G: Clostridium perfringens type A food poisoning. II. Response of the rabbit ileum as an indication of enteropathogenicity of strains of Clostridium perfringens in human beings. Infect lmmunol 3:171-178, 1971 65. Keusch GT, Mata LJ, Grady GF: Shigella enterotoxin : isolation and characterization (abstr) . Clin Res 18:442, 1970 66. Gorbach SL, Banwell JG, Chatterjee BD, et al: Acute undifferentiated human diarrhea in the tropics. I. Alterations in intestinal microflora. J Clin Invest 50:881~889, 1971 67. Dupont HL, Formal SB, Hornick RB, et al: Pathogenesis of Escherichia coli diarrhea. N Eng! J Med 285:1- 9, 1971 68. Shields R, Miles JB, Gilbertson C: Absorption and secretion of water and electrolytes by the intact colon in a patient with primary aldosteronism. Br Med J 1:93-96, 1968 69. Greenough WB III, Pierce NF, AI Awgati 0, et a!: Stimulation of gut electrolyte secretion by prostaglandins, theophylline and cholera exotoxin (abstr). J Clin Invest 48:32a, 1969 70. Gardiner JD, Peskin GW, Cerda JJ, et al: Alterations of in vitro fluid and electrolyte absorption by gastrointestinal hormones. Am J Surg 113:57-64, 1967 71. Barbezat GO, Grossman Ml: Cholera-like diarrhea induced by glucagon plus gastrin. Lancet 2:1025, 1971 72. Barbezat GO, Grossman Ml: Intestinal secretion: stimulation by peptides. Science 174: 422-423, 1971 73. Schmid WC, Phillips SF, Summerskill WHJ: Jejunal sec retion of electrolytes and water in nontropical sprue. J Lab Clin Med 73:772-783, 1969 74. Phillips SF, Schmid WC: Jejunal transpo.rt of electrolytes and water in intestinal disease. Gut 10:990-993, 1969 75. Binder HJ, Ptak T: Jejunal absorption of water and electrolytes in inflammatory bowel disease. J Lab Clin Med 76:915- 924, 1970

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76. Powell DW, Plotkin GR, Maenza RM, et a!: Experimental diarrhea. I. Intestinal water and electrolyte transport in rat Salmonella enterocolitis. Gastroenterology 60:1053-1064, 1971 77 . Carpenter CCJ, Sack RB, Feeley JC, eta!: Site and characteristics of electrolyte loss and effect of intraluminal glucose in experimental canine cholera. J Clin Invest 47 :1210-1220, 1968 78. Hirschhorn N, Kinzie JL, Sachar DB, et al: Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. N Eng! J Med 279:176-181, 1968 79. Nalin DR, Cash RA, Rahman M, et a!: Effect of glycine and glucose on sodium and water absorption in patients with cholera. Gut 11: 768- 772, 1970 80. Powell DW, Plotkin GR, Solberg Ll, et al: Experimental diarrhea. II. Glucose stimulated sodium and water transport in rat Salmonella enterocolitis. Gastroenterology 60:1065-1075, 1971 81. Serebro HA, lber FL, Yardley JH, eta!: Inhibition of cholera toxin action in the rabbit by cyclohexamide. Gastroenterology 56:506511, 1969 82. Field M : Intestinal secretion : Effect of cyclic AMP and its role in cholera. N Eng! J Med 284:1137- 1144, 1971 83. Bayless TM, Paige DM, Ferry GD: Lactose intolerance and milk drinking habits. Gastroenterology 60:605-609, 1971 84. Gryboski JD: Diarrhea from diabetic candies. N Eng! J Med 275:718, 1966 85. Welsh JD, Zschiesche OM, Anderson J , et a!: Intestinal disaccharidase activity in celiac sprue (gluten sensitive enteropathy) . Arch Intern Med 123:33-38, 1969 86. Lindquist B, Meeuwisse G: Glucose galactose malabsorption . Bib! Paediatr 87 :92-100, 1968 87. Laws JW, Nea le G: Radiological diagnosis of disaccharidase deficiency. Lancet 2:139-143, 1966 88. Launiala K : The mechanism of diarrhoea in congenital disaccharide malabsorption . Acta Paediatr Scand 57:425-432, 1968 89. Christopher ML, Bayless TM: Role of the small bowel and colon in lactose induced diarrhea. Gastroenterology 60:845-852, 1971 90. Launiala K: The effect of unabsorbed sucrose and mannitol on the small intestinal flow rate and mean transit time. Scand J Gastroenterol 3:665-671, 1968 91. Torres-Pinedo IR, Lavastida M, Rivers CL, et al: Studies in infant diarrhea. I. A comparison of the effects of milk feeding and intravenous therapy upon the composition and vol ume of the stool an d urine. J Clin Invest 45: 469- 480, 1966

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109. Field M, Fromm D, Wallace K, et al: Stimula92. Torres-Pinedo R, Conde E, Robillard G, et al: tion of active chloride secretion in small intesStudies in infant diarrhea. II. Changes in the tine by cholera exotoxin (abstr) . J Clin Invest compositions of saline and glucose saline solu48:24A, 1969 tions instilled into the colon. Pediatrics 42: 110. Moore WL, Bieberdorf FA, Morawski SG, et 303-311, 1968 al: Ion transport during cholera induced ileal 93. James AT, Webb JPW, Kellock TD: The secretion in the dog. J Clin Invest 50:312-318, occurrence of unusual fatty acids in fecal lipids 1971 from human beings with normal and abnormal 111. Sachar DB, Taylor JO, Saha JR, et al: Intestifat absorption . Biochem J 78:333-339, 1961 nal transmural electrical potential and its re94. Webb JPW, James AT, Kellock TD: Influence sponse to glucose in acute and convalescent of diet on quality of fecal fat in patients with cholera. Gastroenterology 56:512-521, 1969 and without steatorrhea. Gut 4:37-41, i963 95. Kim YS, Spritz N: Hydroxy acid excretion in 112. Binder JH, Powell DW: Bacterial enterotoxins and diarrhea. Am J Clin Nutr 23:1582- 1587, steatorrhea of pancreatic and nonpancreatic origin. N Engl J Med 279:1424-1426, 1968 1970 96. Kellock TD, Pearson JR, Russell RI, et al: The 113. Forth W, Rummel W, Glasner H : Zur resorpincidence and clinical significance of faecal tionschemmenden Wirkung von Gullansauren. hydroxy fatty acids (abstr). Gut 10:1055, 1969 Naunyn Schmiedebergs Arch Pharmakol Exp 97. Thomas PJ : In vitro conversion of oleic acid to Pathol 254:364-380, 1966 hydroxy · stearic acid by intestinal bacteria 114. Mekhjian HS, Phillips SF, Hofmann AF: Colonic secretion of water and electrolytes (abstr). Clin Res 18:609, 1970 98. Kim YS, Spritz N: Metabolism of hydroxy fatty induced by bile acids: Perfusion studies in acids in dogs with steatorrhea secondary to man. J Clin Invest 50:1569-1577, 1971 experimentally produced intestinal blind loops. 115. Dietschy JM: Effects of bile salts on intermediJ Lipid Res 9:487-491, 1968 ate metabolism of the intestinal mucosa. Fed 99. Hofmann AF, Poley JR, Mekhjian HS, et al: Proc 26:1589-1598, 1967 Hydroxy fatty acid-an apparent cause of diar- 116. Clark ML, Lanz HC, Senior JR: Bile salt regulation of fatty acid absorption and esterification rhea in patients with ileal resection and steatorin rat everted jejunal sacs in vitro and into rhea (abstr) . J Clin Invest 49:44a, 1970 thoracic duct lymph in vivo. J Clin Invest 48: 100. Wiggins HS, Howell KE, Kellock TD, et al : 1587-1599, 1969 The origin of fecal fat . Gut 10:400-403, 1969 101. Hadom B, Tarlow MJ, Lloyd JK, et al: Intesti- 117. Hofmann AF : The syndrome of ileal disease and the broken enterohepatic circulation: nal ent.e rokinase deficiency. Lancet 1:812-813, 1969 Cholerheic enteropathy. Gastroenterology 52: 102. Navab F, Asatoor AM: Studies of intestinal 752-757, 1967 absorption of amino acids and a dipeptide 118. Tabaqchali S, Hatzioannou J , Booth CC: Bile in a case of Hartnup disease. Gut 11:373salt deconjugation and steatorrhea in patients 379, 1970 with the stagnant loop syndrome. Lancet 2: 103. Hooft C, Antener I: Methionine malabsorption 12-16, 1968 syndrome. Bibl Paediatr 87:127- 136, 1968 119. lwao I, Terada Y: On the mechanism of diarrhea 104. Phillips RA: Water and electrolyte losses in due to castor oil. Jap J Pharmacol 12:137-145, cholera. Fed Proc 23:705- 712, 1964 1962 105. Gorbach SL: Intestinal microflora . Gastro120. Schmid W: Zum Wirkungsmechanismus diateenterology 60:1110-1129, 1971 tischer und medikamentoser Darmmittel. 106. Banwell JG, Gorbach SL, Pierce MF, et al: Arzneim Forsch 2:6-20, 1952 Acute undifferentiated human diarrhoea in 121. Reynell PC, Spray GH: Chemical gastroenterthe tropics. II. Alterations in intestinal fluid itis in the rat. Gastroenterology 34:867-873, and electrolyte movement. J Clin Invest 1958 50:890-900, 1971 122. Phillips RA, Love AHG, Mitchell TG: Ca107. Banwell JG, Pierce MF, Mitra RC, et al : Inthartics and the sodium pump. Nature (Lond) testinal fluid and electrolyte transport in 206:1367-1368, 1965 human cholera. J Clin Invest 49:183-195, 1970 123. Wollaeger EE, Comfort MW, Osterberg AE: 108. Koya G, Kosakai N, Fukasawa Y: SuppleTotal solids, fat and nitrogen in the feces. mentary studies on the multiplication of EsGastroenterology 9:272-283, 1947 cherichia coli 0-111 B, in the intestinal tract of 124. Annegers JH, Boutwell JH, Ivy AC: The effect adult volunteers and its relation to manifestaof dietary fat on fecal fat excretion and subtions of coli enteritis. Jap J Med Sci Bioi 7: jective symptoms in man. Gastroenterology 655- 661, 1959 10:486-495, 1948

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125. Kasper H: Faecal fat excretion, diarrhea and subjective complaints with highly dosed oral fat intake. Digestion 3:321-330, 1970 126. Watson WC, Gordon RS, Karmen A, et a!: The absorption and excretion of castor oil in man. J Pharm Pharmacol 15:183-188, 1963 127. Hofmann AF, Poley JR: Cholestyramine treatment. of diarrhea associated with ileal resection. N Eng! J Med 281:397-402, 1969 128. Eastwood MA, Eriksson S: The use of lignin in controlling diarrhoea due to ileal dysfunction (abstr) . Gut 11:370, 1970 129. Sandler M, Karim SMM, Williams ED: Prostaglandins in aminepeptide secreting hormones. Lancet 2:1053-1054, 1968 130. Ganesnappa KP, Whalen GE, Meade RC , eta!: The effect of glucagon on jejunal motility, electrolyte and water absorption in man (abstr) . Clin Res 19:658, 1971 131. Huizenga KA, Goodrick WIM, Summerskill WHJ: Peptic ulcer with islet cell tumor: A reappraisal. Am J Med 37:564-577, 1964 132. Shimoda SS, Saunders DR, Rubin CE: The Zollinger-Ellison syndrome with steatorrhea. II. Mechanisms of fat and vitamin B 12 malabsorption. Gastroenterology 55:705-723, 1968 133. Go VLW, Poley JR, Hofmann AF, et a!: Disturbances in fat digestion induced by acidic jejunal pH due to gastric hypersecretion in man. Gastroenterology 58:638-646, 1970 134. Hebert RJ, Gustke RF, Soergel KF: Diarrhea due to gastric hypersecretion (abstr). Clin Res 16:447, 1968 135. Mansbach CM, Wilkins RM, Dobbins WO, et a! : Intestinal mucosal function and structure in the steatorrhea of the Zollinger-Ellison syndrome. Arch Intern Med 121:487-494, 1968 136. Adibi S, Ruiz C, Glaser P, eta!: Effect of variation in intraluminal pH on absorption of amino acid, water and electrolytes in human jejunum (abstr). Clin Res 19:654, 1971 137. Castell DO, Cohen S, Harris LD: Response of human ileocecal sphincter to gastrin. Am J Physiol 219:712-715, 1970 138. Tompkins RK, Kraft AR, Zollinger RM: Secretin-like choleresis produced by diarrheogenic non-beta islet cell tumor of the pancreas. Surgery 66:131-137, 1969 139. Sircus W, Brunt PW, Walker RJ, et a!: Two cases of "pancreatic cholera" with features of peptide secreting adenomatosis of the pancreas. Gut 11 :197- 205, 1970 140. Cleator IGM, Thomson CG, Sircus W, et a!: Bio-assay evidence of abnormal secretin-like and gastrin-like activity in tumour and blood in cases of "choleraic diarrhoea." Gut 11:206211 , 1970 141. Rummel W, Stupp HF: The influence of diu-

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retics on absorption of salts, glucose and water from the isolated small intestine of the rat. Experientia 18:303-308, 1962 142. Soergel KH, Whalen GE, Harris JA, et a!: Effect of antidiuretic hormone on human small intestinal water and solute transport. J Clin Invest 47:1071-1082, 1968 143. Gamble JL, Fahey KR, Appleton J, et a!: Congenital alkalosis with diarrhea. J Pediatr 26: 509-518, 1945 144. Evanson JM, Stanburg SW: Congenital chloridorrhoea or so-called congenital -alkalosis with diarrhea. Gut 6:29-38; 1965 145. Bieberdorf FA,· Gordon P, Fordtran JS, et a!: Pathogenesis of congenital alkalosis with diarrhea (abstr). Clin Res 19:386, 1971 146. Shnitka JK, Friedman MHW, Kidd EG, et a!: Villous tumours of the rectum and colon, characterized by severe fluid and electrolyte loss. Surg Gynecol Obstet 112:609- 621, 1961 147. Little JM: Potassium imbalance and rectosigmoid neoplasia. Lancet 1:302-303, 1964 148. Crane CW: Observations on the sodium and potassium content of mucus from the large intestine. Gut 6:439-443, 1965 149. Duthie HL, Atwell JD: The absorption of water, sodium and potassium in the large intestine with particular reference to the effects of villous papillomas. Gut 4:373-377, 1963 150. Waldmann TA, Wochner RD, Laster L, et a!: Allergic gastroenteropathy. N Eng! J Med 276: 761-769, 1967 151. Greenberger MJ, Tannenbaum JI, Ruppert RD: Protein losing enteropathy associated with gastrointestinal allergy. Am J Med 43:777784, 1967 152. Head LH, Heaton JW Jr, Kivel RM: Absorption of water and electrolytes in Crohn's disease of the colon. Gastroenterology 56:571-579, 1969 153. Harris J, Shields R: Absorption and secretion of water and electrolytes by the intact human colon in diffuse, untreated proctocolitis. Gut 11:27- 33, 1970 154. Atwell JD, Duthie HL: The absorption of water, sodium and potassium from the human ileum showing the effects of regional enteritis. Gastroenterology 46:16-22, 1963 155. Jalan KM, Walker RJ, Prescott RJ, et a!: Faecal stasis and diverticular disease in ulcerative colitis. Gut 11:688-696, 1970 156. Lennard-Janes JE, Langman MJS, Jones FA: Faecal stasis in proctocolitis. Gut 3:301- 305, 1962 157. Fordtran JS, Rector FC, Locklear TW, et al: Water and solute movement in the small intestine of patients with sprue. J Clin Invest 46:287-298, 1967

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158. Wa pnick S, Mantoudis SM, Cox AG: Functional compensation in the first twelve weeks after small intestinal resection in the rat. Br J Surg 56:864-866, 1969 l!i9. Walker-Smith J, Wyndham N: Total loss of mid-gut. Med J Aust 1:857- 860. 1967 160. Wright HK, Cleveland JC, Tilson MD, et al: Morphology and absorptive capacity of the ileum after ileostomy in man . Am J Surg 117: 242- 245, 1969 161. Wilmore DW, Dudrick SJ, Daly JA, et al: The role of nutrition in the adaptation of the small intestine after massive resection. Surg Gynecol Obstet 132:673- 680, 1971 162. Anderson CM: Long term survival with six inches of small in testine. Br Med J 1:419- 422, 1965 163. Venables CW, Ellis H , Smith ADM: Antiperistaltic segments after massive intestinal resections. Lancet 2:1390- 1394, 1966 164. Poth EJ: Use of gastrointestinal reversal in surgical procedures. Am J Surg 118:893- 899, 1969 165. Waddell WR, Kern F , Dalgrimson CG, et al: A simple jejunocolic "valve. " Arch Surg 100:438444, 1970 166. Dixon JMS: The fate of bacteria in the small intestine. J Pathol Bacterial 79:131- 140, 1960 167. Ament ME, Shimoda SS, Saunders DR, et al: The pathogenesis of steatorrhea in stasis syndrome (abstr). Gastroenterology 60:637, 1971 168. Low-Beer T, Schneider RE, Dobbins WO: Morphological changes of the small intestinal mucosa of guinea pig and hamster following incubation in vitro and perfusion in vivo with unconjugated bile acids. Gut 11:486- 492, 1970 169. Connell AM: The motility of the sma ll intestine. Postgrad Med J 37 :703-716, 1961 170. Dillard RL, Eastman H , Fordtran JS: Volume flow relationships during the transport of fluid through the human small in testine. Gastroenterology 49:58-66, 1965 171. Shehadeh Z, Grantham RM, Brecher GA, et al: The effects of infusion rate and osmolality on volumogenic diarrhea. Gastroenterology 57 :24- 29, 1969 172. Grantham RN, Brecher GA, Jacobson ED: Fluid dynamics in volumogenic diarrhea. Digestion 3:1- 12, 1970 173. Farrar JT, Zafass AM : Small intestinal motility. Gastroenterology 52:1019- 1037, 1967 174. Bennett A, Fleshier B: Prostaglandins and the gastrointestinal tract. Gastroenterology 59: 790- 800, 1970 175. Misiewicz JJ, Walker SL, Kileg N, et al : Effect of oral prostaglandin E 1 on intestinal transit in man. Lancet 1:648-651, 1969

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176. Connell AM: The motility of the pelvic colon. II. Paradoxical motility in diarrhea and constipation. Gut 3:342- 348, 1962 . 177. Gorbach S: Acute diarrhea-a ',' toxin " disease. N Eng! J Med 283:44-45, 1970 178. Yow MD, Malnick L Jr, Blattner RJ, eta! : The association of viruses and bacteria with infantile diarrhea. Am J Epidemiol 92:33-39, 1970 179. Cramblett HG, Azini P , Haynes RE: The etiology of infectious diarrhea in infa ncy with special reference to enteropathogenic E. coli. Ann NY Acad Sci 176:80- 92, 1971 180. Hooper BE, Haelterman EO: Lesions of the gastrointestinal tract of pigs infected with transmissible gastroenteritis. Can J Comp Med 33:29- 36, 1969 181. King MJ, Joske RA: Acute enteritis with temporary intestinal malabsorption. Br Med J 1:1324-1327, 1960 182. Alpers DH, Isselbacher KJ: Disaccharidase deficiency. Adv Metab Dis 4:7.')-122. 1970 183. Marsden PD, Schulz MG: Intestinal parasites. Gastroenterology 57:724-750, 1969 184. Whalen GE, Rosenburg EB, Strickland GT, et al: Intestinal capillariasis: A new disease in man. Lancet 1:13-16, 1969 185. Leon-Ba rua R: The possible role of intestinal bacterial flora in the genesis of diarrhea and malabsorption associated with parasitosis. Gastroenterology 55:559, 1968 186. Vogt W, Schmidt G, Dakhel T: Die Bedautung der Glucuronidbildung und-Spaltung fur das Schietzsal von Dihydroxy-diphenylmethan. Naunyn Schmiedebergs Arch Pharmakol Exp Pa thol 250:488- 495, 1965 187. Heizer WD, Warshaw AL, Waldmann TA, et al: Protein losing gastroenteropathy and malabsorption associated · with factitious diarrhea. Ann Intern Med 68:839-852, 1968 188. Fleischer M , Brown H, Graham DY, et al : Chroni c laxative induced hyperaldosteronism and hypokalemia simula ting Bartter's syndrome. Ann Intern Med 70:791- 798, 1969 189. Deller DJ: Functional and metabolic results of partial gastrectomy. Med J Aust 1:405-410, 1965 190. Lundh G: Mechanism of postgastrectomy ma labsorption. Gastroenterology 42:637-640, 1962 191. Kinsella VJ , Hennessy WB, George EP: Studies on post gastrectomy malabsorption : Importance of bacterial contamination of upper small intestine. Med J Aust 2:257- 261, 1961 192. Midtvedt T, Norman A, Nygaard K: Metabolism of glycocholi c acid in gastrectomized patients. Scand J Gastroenterol 5:237-240, 1970

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193. Gudmond-Hoyer E: Lactose malabsorption after gastric surgery. Digestion 2:289-297, 1969 194. Phillips SF: Absorption and secretion by the colon. Gastroenterology 56:966-971, 1969 195. Heaton KW, Read AE: Gallstones in patients with disorders of the terminal ileum and disturbed bile salt metabolism. Br Med J 2:494496, 1969 196. Spiro H: Clinical Gastroenterology. Toronto, Macmillan Co, 1970, p 701-702 197. Williams JA, Cox AG: After Vagotomy. London, Butterworth, 1969 198. Gamble WS : Impaired pancreozymin (CCKPZ) secretion after vagotomy and pyloroplasty (abstr). J Lab Clin Med 76:871, 1970 199. Shields R, Miles JB: Absorption and secretion in the large intestine. Postgrad Med J 41:435439, 1965 200. DiMagno EP, Go VLW, Summerskill WHJ: Pancreozymin secretion is impaired in sprue (abstr) . Gastroenterology 56:1149, 1969 201. Low-Beer TS, Heaton KW, Heaton ST, et al: Gallbladder inertia and sluggish enterohepatic circulation of bile salts in coeliac disease. Lancet 1:991- 994, 1971 202. Waldmann T: Protein losing enteropathy. Gastroenterology 50:442-443, 1966 203. Salem SN, Truelove SC: Small intestinal and gastric abnormalities in ulcerative colitis. Br Med J 1:827- 831, 1965 204. Newcomer AD, McGill DB: Incidence of lactase deficiency in ulcerative colitis. Gastroenterology 53:890-893, 1967 205. Whalen GE, Soergel KH, Geenan JE: Diabetic diarrhea : A clinical and pathophysiological study . Gastroenterology 56:1021-1032, 1969 206. McBrien DJ, Vaughn Jones R, Creamer B: Steatorrhea in Addison's disease. Lancet 1: 25-26, 1963 207. Levitan R, lngelfinger FJ: Effect of d-aldosterone on salt and water absorption from the intact human colon. J Clin Invest 44:801-808, 1965 208. Baker JT, Harvey RF: Bowel habit in thyrotoxicosis and hypothyroidism. Er Med J 2:322323, 1971 209. Christensen J, Schedl HP, Clifton JA: The basic electrical rhythm of the duodenum in normal human subjects and in patients with thyroid disease. J Clin Invest 43: 1659-1667, 1964 210. Chaudhary MA, Truelove SC : Colonic motility. A critical review of methods and results. Am J Med 31:86- 106, 1961 211. Weser E, Rubin W, Ross L, et al: Lactase deficiency in patients with "irritable colon syndrome." N Eng! J Med 273:1070-1074, 1965

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