Chronic nonspecific diarrhea (CND) represents one of the more frequent gastrointestinal complaints in childhood and is a major cause of anxiety among parents and physicians. CND appears to be one manifestation of the common functional gastrointestinal disorder, the irritable bowel syndrome (IBS). The frequent occurrence of IBS among family members and the strong possibility that children with CND will continue to have symptoms of IBS emphasize the chronic nature of this condition.
Originally described by Cohlan1 and Davidson and Wasserman,2 CND is distinguished from intractable diarrhea by lack of any evidence of malabsorption, growth retardation, or dehydration. The onset of symptoms occurs classically between 6 and 20 months of age with spontaneous resolution by 40 months of age in over 90% of patients. Bowel movements are described as painless diarrhea occurring three to six times a day with undigested food and mucus. In some children, the diarrheal episodes are intermittent and recurrent, with each episode lasting a few days to a few weeks. The majority of patients will have a large, often well formed stool as their first bowel movement of the day. Subsequent stools are smaller, looser and contain more mucus and vegetable fiber. Blood is rarely present in the stools and, when found, is usually associated with fissures or excoriations. Respiratory infections, periods of teething, immunizations, and other physical stresses are frequently associated with exacerbations of diarrhea. A majority of children with CND will have difficulties with constipation as they grow older. In the original study, 122 of 153 patients developed constipation on follow-up. 2 In many cases there is a significantly family history of functional bowel complaints; 67% of all family members in the original study had a history of either constipation or diarrhea.2 In addition, there is often a past history of colic with feeding difficulties and explosive stools during the first few months of life, usually followed by a symptom-free interval before the development of the characteristic diarrhea pattern.
The average adult ingests approximately 2 liters of fluid per day. Seven additional liters of salivary, gastric, biliary, pancreatic, and intestinal fluid are also secreted into the intestine.3 In normal humans, 95% to 98% of the intestinal fluid is reabsorbed.4 The distal colon is the site of final stool dessication. Stool contents arriving in the distal colon are always liquid and contain mucus and vegetable residue. The final conversion of this liquid mass to well formed stool is facilitated in the distal colon by characteristic tonus contractions of the colonic musculature.5 Together with segmental and propulsive waves, the tonus contractions constitute the three patterns noted in the colon.6 Tonus contractions are nonpropulsive and of long duration. Segmental contractions are primarily concerned with mixing and churning bowel contents, while propulsive movements are highly coordinated and propel colonic contents distally in response to stimuli such as food intake. In the distal colon, the predominance of the tonus contractions leads to narrowing of the intestinal lumen and subsequent increased contact between the luminal contents and the intestinal absorptive surface.7 Colonic receptors are stimulated and the urge to defecate is appreciated at a set level of colonic tonic activity. This level appears to be constant for each individual but varies from one person to the next.8
Many factors influence colonic motility; these include food intake, physical activity, the autonomic nervous system, and emotional and psychological factors. Feeding results in an increase in the propulsive movements, a finding that is commonly termed the gastrocolic reflex.9 Physical activity also stimulates colonic activity.6 The influence of the autonomic nervous system is complex. Studies have suggested that cholinergic agonists stimulate and anticholinergics and adrenergic agents inhibit contractile activity.10,11 Finally, Almy et al12 demonstrated that emotional and psychological factors significantly influence colonic contractile activity, specifically the amplitude and frequency of tonus contractions.
As originally suggested by Davidson and Wassermann CND appears to be a childhood manifestation of the lifelong condition, IBS. The significant propensity for these children to suffer from IBS as they grow older supports the concept that the underlying pathophysiologic processes are similar in both CND and IBS. Several abnormalities of colonic motility have been demonstrated in patients with IBS. These changes were first described by Almy in the late 1940s. He showed that patients with "spastic" colon had a marked increase in motility. This motility pattern has been implicated in the constipation seen in these patients. 12,13 Connell et al14 have shown that in response to food, patients with IBS develop marked overactivity of colonic motility and increased pressure in the sigmoid colon. In addition, patients with IBS have been shown to have significant colonic hypermotility in response to parasympathomimetic drugs15 and to the hormone cholecystokinin.16 Finally, Almy12 showed that the patient's emotional state has a major impact on the colonic musculature and that stress situations may precipitate disturbances in colonic motility.
Recent work has demonstrated that there is abnormal myoelectrical activity in IBS. The intestinal smooth muscle cell exhibits a fluctuating basic electrical rhythm (BER). In the colon, the BER is of two types, a faster rhythm (frequency 6 to 9 cycles/min) and a slower rhythm (2.5 to 4 cycles/min). Snape et al17 have shown that unlike normal patients, where only 10% of the total BER activity is the slower rhythm, patients with IBS have approximately 40% of the total BER as 3 cycle/min activity. This abnormality of the BER has been shown to be specific for IBS and is not merely a feature of altered bowel habits. 18 It has been shown that colonic responsiveness to pentagastrin is dependent upon the 3 cycle/min rhythm. In patients with IBS, stimulation with cholecystokinin or pentagastrin resulted in a significant increase in the slower BER.19 These authors have suggested that the increase in colonic 3 cycle/min slow wave activity may be the basic abnormality in IBS. This abnormality leads to colonic motor dysfunction in response to a variety of physiologic stimuli.20
Other studies have focused on the decreased transit time observed in these patients and the possibility of disordered small intestinal motility. Fenton et al21 demonstrated that unlike normal children, patients with CND failed to disrupt the normal migrating motor complex in response to intraduodenal dextrose. They suggested that this could result in a marked increase in the transit rate of small intestinal contents and an increase in the delivery of partially digested food to the colon.
Additional studies have focused on the small intestine as the pathogenic site of this disease. Tripp et al22 found evidence for a significant increase in adenyl cyclase and Na K+ -ATPase activity in small intestinal biopsies taken from children with CND. Dodge et al23 have shown that children with CND have elevated levels of the prostaglandin PGF2. Some authors have suggested that the increased enzyme activity is mediated via these elevated prostaglandins and that these changes may result in altered small intestinal motility.24
Dietary factors may play a role in initiating CND as well as prolonging the diarrheal state. Greene and Ghishian25 have suggested that a large percentage of children with CND were consuming large amounts of fluid, usually as treatment for acute infectious gastroenteritis. They postulated that this excessive fluid intake may overwhelm the absorptive capacity of the intestinal tract and result in continued diarrhea. Others have suggested that prolonged use of elimination diets, initially prescribed for acute diarrheal episodes, can result in nutritional damage to the intestinal mucosa and prolongation of diarrhea.26 Finally, Cohen et al27 have shown that the majority of their patients with CND had diets containing less fat than is recommended for their age. Dietary modifications in those patients resulted in normalization of bowel movements within three to 14 days. The authors suggested that fat consumption alters the stool pattern via an effect on intestinal motility.
Differential Diagnoses of Chronic Nonspecific Diarrhea
As the treatment of CND is supportive, the physician caring for a child with this disorder must be confident that other, less benign conditions have been ruled out. Therefore, the possibilities of malabsorpti ve conditions or chronic infections must be considered in all children who present with chronic diarrhea (Table). The most important aspect of the evaluation in these patients is a careful, detailed history with specific emphasis on growth parameters and stooling patterns. In any child who is not following his or her weight and height curves malabsorption must be suspected. In addition, further tests should be considered for any patient with diarrhea that began before 6 months of age, is described as "greasy," "fatty," or significantly "foul-smelling," or is related to a specific food such as wheat or cow's milk.
The initial workup for malabsorption includes measurements of serum proteins, liver function, calcium, phosphate, and cholesterol as well as serum hemoglobin and lymphocyte count. A screening stool examination is also used. The physician examining the stool should first note its appearance to confirm the historical information obtained from the parent. The stool should also be tested for guaiac positivity. A Wright stain will disclose the presence of inflammatory cells that may be seen in intestinal infections or inflammation. If carbohydrate intolerance is suspected, a test for stool pH and reducing substances should be done. If sucrose intolerance is suspected, the stool must be acid hydrolyzed prior to Clinitest® testing. In laboratories where fat staining is routinely done, Sudan red staining of a stool specimen can be helpful in screening for steatorrhea. The presence of chronic infections can be determined by obtaining stool cultures for Salmonella, Shigella, Campylobacter, and Yersinia as well as stool ova and parasites for Giardia. Finally, a careful dietary history with specific emphasis on calorie intake should be reviewed in any child with inadequate growth.
Further evaluations in these children should be determined based on the initial workup. Any child with poor weight gain, suspected malabsorption, or onset of diarrhea before 6 months of age should have a sweat test for cystic fibrosis. A history of chronic infections with low serum protein may be seen in children with chronic diarrhea that is secondary to an underlying immunodeficiency. In these children, immunoglobulin levels should be determined. Thyroid function tests should be obtained in any child with clinical evidence of hyperthyroidism. Recent studies have demonstrated that a D-xylose absorption test is an ideal screening test for small intestinal mucosal diseases such as celiac disease or allergic gastroenteropathy.28 Alternatively, 72 hour fecal fat collection can be used to determine the presence or absence of steatorrhea. In patients who have guaiac positive stools or significant amounts of inflammatory cells on Wright stain, a colonoscopy or sigmoidoscopy may demonstrate colitis. In children of this age group, colitis can be secondary to milk ingestion, antibiotics, intestinal infection, or an idiopathic disease. Finally, disacharidase deficiency can be confirmed by evidence of carbohydrate intolerance in the stool as well as by breath hydrogen determinations after ingestion of the specific carbohydrate.
Treatment of children with CND is designed with the knowledge that these patients do not have an underlying disorder that will affect their growth and nutrition. Therefore, initial therapeutic measures include parental reassurance with a sympathetic, supportive family-physician relationship. In view of the evidence that anxiety has an adverse effect on colonic motility,12 an improvement in familial stress will often be reflected in a decrease in stool frequency. Proper dietary counseling is crucial in view of studies that have implicated increased fluid intake, fat restriction and elimination diets in the pathogenesis of CND. Green and Ghishan25 showed that normalization of fluid intake resulted in improvement in 18 of 18 children with CND who had been consuming excess fluid. Cohen et al27 demonstrated that a therapeutic diet deriving 30% to 50% of its calories from fat resulted in resolution of diarrhea in 80% of children with CND. Davidson and Wasserman2 showed that an unrestricted diet resulted in normalization of bowel movements in 80% of patients. Other studies have suggested that the introduction of cold material into the stomach stimulates colonic motility.29 Therefore, chilled foods should be eliminated from the child's diet.
A large variety of medications have been used to treat children with CND. Due to the benign nature of CND, it is generally felt that there is no place for drug therapy in this condition.30 Children with significant cramping may benefit from a high fiber diet with the addition of bran or psyllium seed preparations.
The finding that 122 of 153 patients developed constipation on follow-up emphasizes the chronic nature of this condition.2 Taylor et al20 showed that there is no difference in transit time or stool weight in patients with IBS before or after treatment. In addition, the abnormal myoelectrical activity did not return to normal in these patients despite symptomatic improvement. These findings demonstrate that there is a fixed abnormality in patients with CND and IBS, which helps explain the tendency toward relapse. However, the lack of malabsorption, growth retardation, or dehydration is reassurance that CND is a condition for which the best treatment regimens do not employ medication. Frank discussion together with the need for an unrestricted diet provide the best solutions.
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Differential Diagnoses of Chronic Nonspecific Diarrhea