Chronic diarrhea is one of the most perplexing problems for physicians to evaluate. The difficulty arises because physicians believe that the differential diagnosis is long and they often don't know what are the best, or first, diagnostic studies to establish a diagnosis. Surprisingly, over 95 percent of patients with chronic diarrhea fit into a few specific diagnostic categories.
Diarrhea is considered chronic if formless stools are passed for 14 or more days. Some patients with chronic diarrhea have it intermittently - with days or weeks of diarrhea alternating with days or weeks of normal stool.
Evaluation of the patient with chronic diarrhea begins with a careful history and physical examination. The most important data obtained from the history are a thorough dietary record and chronological plots of head size, height, and weight. Changes in the diet should be correlated with stool frequency and form. In infants, careful notes should be taken as to whether breast feeding or formula was fed initially and what effects diet changes may have had on the infant. In older children, attention must be paid to the fat and fiber content of the diet. The physician or physician's assistant should inquire about the types of bread, cereal, fruits and vegetables eaten. Information regarding variations in protein, carbohydrate and fat content of foods and formulas is available and is critical to interpreting dietary history.
While many nutritional assessment parameters exist, weight for height is the best single index of growth failure secondary to malnutrition. Mid-arm circumference and triceps skin-fold thickness, although indicative of muscle mass and fat stores, may be falsely increased if the patient is hypoproteinemic.
Periods of poor weight gain may be due to malabsorption or lack of caloric intake. A common mistake is failure to appreciate that rather than because of malabsorption, lack of progress on the growth curve may be due to the feeding of dilute hypocaloric formula or clear liquids in an effort to reduce diarrhea.
A history of exposure to infectious agents may also be crucial. Travel to foreign countries or to areas where there may be contamination of water supply and food within two weeks prior to the onset of diarrhea may be important Inquiries should also be made about camping or hiking activity prior to the onset of the illness as well as to whether other family members may have had any gastrointestinal symptoms of diarrhea, cramping, abdominal pain or vomiting. Time spent in day-care centers or with baby sitters taking care of large numbers of infants may represent exposure to giardiasis and may, therefore, be important. Exposure to antibiotics within six weeks of onset of diarrhea is critical because the diarrhea is often delayed and the association forgotten.
Family history should determine if relatives may have had chronic diarrhea, cystic fibrosis, celiac sprue, protein intolerance, or disaccharidase deficiencies in older children. A family history of Crohn's disease or ulcerative colitis may be important.
A careful description of the stool should be obtained in language familiar to the parents. The physician should inquire if the stool is gray-green, shiny, and whether oil droplets have been seen. If the latter compliant is made, it is indicative of exocrine pancreatic insufficiency. Parents who comment that stool odor is extremely foul and "may be smelled from a room away" usually are indicating the presence of steatorrhea. A stool with little or no odor or a yeasty odor may be more indicative of carbohydrate malabsorption. A putrid or purulent odor with blood streaking or mucus is more typical of colitis.
The most critical part of the physical examination is the current anthropometric measurements: weight for age, height for age, weight for height and comparing this data to previous measurements.
Cheilosis and a smooth red tongue suggest vitamin B deficiency; hemorrhages in the skin indicate vitamins C and K deficiencies. Dry, scaly flaking skin may indicate either essential fatty acid or vitamin A deficiency. Enlargement of the liver and spleen and thinning of the hair may be seen with protein malnutrition; severe protein deficiency may cause peripheral edema and depigmentation.
Nasal polyps and rectal prolapse with localized pulmonary rales may indicate cystic fibrosis. Abdominal distention with a succussion splash may indicate malabsorption. Clubbing of fingers or toes indicates inflammatory bowel disease, or malabsorption syndrome; iritis or arthritis is indicative of inflammatory bowel disease.
A stool specimen should be examined by a physician. This may be obtained by collecting fresh stool from the diaper of an infant, in a stool-collecting receptacle for an older child, orón a gloved fmger following rectal exam at any age. The sample should be inspected for color, consistency, odor, fat droplets, gross blood, or mucus. Grayish stools or stools with an oily sheen may indicate the presence of excess fat; stool that has a rancid odor and can be smelled from across the room indicates steatorrhea; stools with acidic or yeasty odors are typical of carbohydrate malabsorption.
The presence of fat droplets indicates a deficiency in the luminal phase of absorption, implying lack of pancreatic enzymes or bile salts. The presence of gross blood or mucus could mean the patient has either infectious, idiopathic, drug-induced, or formula-induced colitis. Mucus may also be present with chronic nonspecific diarrhea of infancy or with the irritable bowel syndrome.
Simple and helpful chemical tests may be done in the office. The stools should be tested for pH, reducing and non-reducing sugars, occult blood, fat globules, and leukocytes. Stool pH is best determined by using pH paper with a range of 4.5 to 8.0. The paper needs to be touched to a watery component of the stool. Normally, stool may have a pH as low as 5.0 for the first 30 days of life. After this, the pH should be 6.0 or above; stool pH lower than normal suggests carbohydrate malabsorption. If the patient has been on antibiotics during the week prior to stool testing, the colonie flora may be altered. In this case, the pH may not be reflective of carbohydrate malabsorption.
The presence of reducing sugar (lactose, galactose, maltose, fructose, and glucose) may be detected by mixing six drops (or 1.0 ml) of liquid stool with 12 drops (2.0 ml) of water, and adding a Clinitest® tablet. Sucrose may be detected by acid hydrolysis to glucose and fructose. The 1 .0 ml of stool water is mixed with 2.0 ml of 1 N HCl and heated for one minute over the Bunsen burner. After the mixture has cooled, the Clinitest tablet is added. The tablet makes the mixture boil, and the reaction proceeds until 15 seconds after the boiling has stopped. Colorimetrie reading of 0.5 percent or greater is indicative of significant carbohydrate malabsorptionreflecting small intestinal mucosal damage, disaccharidase deficiency, or monosaccharide transport defects.
Blood may be detected by using Hemoccult paper. A speck of stool is added to the hemoccult paper, water is added to saturate the pad, and the developing solution is applied. Bluish discoloration after three seconds indicates 4+ blood; color changes after ten secondsareinsignificant. Blood in the stools suggests a mucosal breakdown along the GI tract, and is typically found in diseases that involve the colon rather than the small intestine.
Leukocytes may be seen by adding two drops of methylene blue to a speck of stool mucus on a glass slide. A cover slip is applied, and the slide is examined under the microscope. Normal stool may have an occasional lymphocyte, but no other cells. The presence of polymorphonuclear leukocytes (PMNs) is typical of either enteritis, colitis or both, due to infection, drugs, formula protein intolerance, or ulcerative colitis or Crohn's disease. Sheets of PMNs are typical of shigellosis, but they may also be seen in severe cases of colonie inflammatory bowel disease, cow's milk and soy protein enterocolitis, G. lamblia or E. hìstolytica infection. Trophozoites, cysts, or fat globules may also be seen in these stained wet mounts. If no fat globules are seen, a stool sample should be examined with a Sudan stain. Fats hydrolyzed by intraluminal pancreatic enzymes and bile salts will be detected on simple staining. The presence of fat globules is suggestive, but not proof, of steatorrhea. The absence of fat globules may indicate either that the patient has no malabsorption or that fat ingestion has been limited.
With this data in hand, the possibilities among the list of differential diagnoses may be narrowed considerably. Patients may be conveniently separated into three age groups: From birth to four months; four months to three years; and four to 18 years.
DETERMINING THE DIAGNOSIS
* From birth to lour months. In the first group, from birth through the first four months of life, chronic diarrhea is likely to indicate a serious absorptive defect and may require extensive investigation. If the diarrhea begins before the first cow's milk formula or breast feeding but after dextrose water is given, the physician must think of an anatomical defect or an abnormality in monosaccharide transport mechanisms. If the diarrhea does not become apparent until after formula feeding is established, the cause is more likely due to: 1) a formula protein intolerance; 2) a congenital absence of disaccharidases; or 3) a defect in monosaccharide transport.
* Formula protein Intolerance. Very young infants who develop diarrhea with PMNs and gross blood in the stool, who are not infected with invasive bacterial organisms, are likely to be reacting to the protein in the formula. They may or may not have evidence of malabsorption. The frequency of protein sensitization in the neonate probably results at this age from the permeability to intact protein of the gastrointestinal mucosa. The spectrum of protein sensitivity in the neonate may range from occult blood loss to severe diffuse enterocolitis. The more severe form may require parenteral nutrition until the mucosa heals. In less severe forms, intactprotein-formuia feedings may be discontinued and the patient fed dextrose and electrolytes for 24 hours, or until blood and white cells disappear from the stool. At that point, feeding with dilute formulas containing hydrolyzed protein or a balanced amino acid solution should be instituted, and gradually advanced until full caloric intake has returned. The diagnosis of protein sensitivity may be established by challenging the patient in a controlled setting after healing has occurred.
After tolerance to the disaccharide present in the offending formula has been documented by a tolerance test, the complete formula is refed - beginning with very small amounts and gradually increasing. Malabsorption of the carbohydrate in the offending formula will serve as a marker of mucosal injury. The dose is continued until tolerance is documented at five days, or vomiting and /or diarrhea develop. This rechallenge must be undertaken with the utmost care, since anaphylaxis may occur. Some investigators have used a single large feeding of 100 ml of the suspected formula for a test dose. When an infant is rechallenged, all stools are examined in a standard manner and are checked for pH, reducing and nonreducing sugars, occult and gross blood, and fecai leukocytes. Two stools in a row that are acidic and show 0.5 percent reducing sugars with or without occult or gross blood are indicative of formula protein intolerance. Fifty percent of infants intolerant to cow's milk protein will react in a similar manner to soy protein and /or goat's milk. Pregestimil®, Vivonex® and Nutramigen® are the best choices to feed an infant suspected of a protein intolerance.
* Absorptive defects. The sudden onset of diarrheal illness in a previously well baby suggests an infectious agent. Viral infections in the first few months of life may produce lesions in the small bowel resulting in persistent malabsorption. The histology of the small bowel may show complete flattening of the villi with marked inflammatory infiltration in the lamina propria. Recovery of bowel function may be compromised by malnutrition, and the child may require prolonged nutritional support with parenteral feeding or continuous drip enteric formulas before recovery occurs.
* Cystic flbrosis. Cystic fibrosis may be difficult to diagnose in the neonate because small babies may not produce sufficient sweat to measure electrolytes accurately. They may present with diarrhea and malabsorption, frequently have voracious appetites and constantly cry - wishing to be fed despite their large food intake. Their stools should be tested for the presence of trypsin and chymotrypsin. Very low levels may be taken as presumptive evidence for the diagnosis; however, confirmation requiresa positive sweat test. A therapeutic trial of pancreatic enzymes may be given until they are old enough to sweat.
* Short bowel syndrome. The short bowel syndrome may follow resection of the bowel forjejunal atresia, ileal atresia, or necrotizing enterocolitis. It has also been described in infants with congenitally shortened bowel. A similar situation exists in those rare infants with hypoplasia of the small bowel villi.
In the short bowel syndrome, the development of diarrhea may depend on the length of remaining small intestine, its functional capacity, and the presence or absence of an ileocecal valve. The ileocecal valve is quite critical to survival. There is a 90 percent chance of long-term survival if the ileocecal valve is intact and there is at least 40 cm of jejunum.
In some instances diarrhea and malabsorption may result from gastric hypersecretion. After resection of 50 percent or more of the small intestine, serum gastrin may rise and normal small bowel inhibition of acid secretion may be impaired. If hypersecretion results in acidification of the small bowel, it may damage proximal duodenal mucosa, inactivate pancreatic enzymes, and precipitate bile salts. Other absorptive defects may arise from reduction of bile salts below critical micellar concentrations due to lack of terminal ileal transport, motility abnormalities, and small bowel overgrowth with bacteria.
Feeding any patient with the short bowel syndrome should be accomplished by continuous intragastric infusion to maximize utilization of limited absorptive surface and minimize diarrhea and malabsorption. Hypo- or iso-molar formulas that are lactosefree, or elemental formulas, may be chosen based on the extent of resection. In many cases, all attempts to aliment enterally will fail and pa rentera t nutrition must be used.
* Transport defect. Neonates who develop diarrhea with the initial glucose water feeding may be suspected of a congenital transport defect. Patients with a congenital glucose-galactose malabsorption should have a flat glucose tolerance test with strongly Clinitest - positive acidic stools. A normal fructose tolerance test would distinguish these individuals from those with mucosal disease. Diagnosis can be confirmed by measuring in vitro glucose transport abnormalities in small bowel tissue obtained by biopsy. Infants who fail both glucose and fructose tolerance tests have either severe mucosal injury, congenital short bowel, or failure to develop villi. Small bowel biopsy and upper intestinal radiography are required for confirmation.
* Disaccharidase deficiencies. Infants with congenital disaccharidase deficiencies rarely present with diarrhea the first four months of life. Since sucrase-isomaltase deficiency is the most common disaccharidase deficiency, and because sucrose is not commonly fed to newborns, sucrase-isomaltase deficiency often does not present for weeks or months after sucrose is added to the diet. Congenital laclase deficiency is extremely rare. Both require a measurement of disaccharidase activity in biopsy samples for confirmation of diagnosis.
* From four months to three years. In infants from four months to three years of age, the causes of diarrhea are somewhat different than in the younger group. A persistent severe malabsorption can result from viral illness in infants over four months old, but this is uncommon. Chronic nonspecific diarrhea of infancy, or irritable bowel syndrome, is the second most common cause of diarrhea in this age group. The most common presentation is a child with a history of abnormal amounts of formless stool who does not show any evidence of malnutrition. If the child shows deficits in weight for height, it is almost always a result of caloric restriction due to substitution in the diet of dilute formulas of glucose water. Dietary restriction in an effort to avoid food allergy also may result in caloric deprivation.
Despite persistence of diarrhea, the child seems to remain healthy and active. Most children tend to come from relatively well-to-do white middle class backgrounds. Some of their mothers seem to be excessively fastidious. The concern they express over the child's condition often appears substantially greater than the physical illness would warrant. The infant passes the greatest amount of stool in the morning, and rarely, if ever, awakens at night to pass stool. For lack of a better term, this constellation of findings has been lumped under the diagnostic category of chronic nonspecific diarrhea of infancy (CNSD). The syndrome may arise following a bout of viral gastroenteritis or antibiotic administration for localized bacterial infection. It seems to occur after the ingestion of foods presumed to produce an allergic response. The small bowel function remains suficient to support normal health and growth if adequate nutrients are provided. Once the adequacy of small bowel function is confirmed, and the various forms of colitis are ruled out by the proctosigmoidoscopy and rectal biopsy, the diagnosis of CNSD is secure.
The irritable bowel syndrome is the most common cause of chronic diarrhea in adult patients. Whether this condition occurs in infancy and is related to CNSD is not clear. Infants with CNSD have not yet been shown to be the same patients who progress to irritable bowel syndrome in adulthood. In contrast to the adult irritable bowel syndrome, which seems to be persistent throughout life, the natural history of CNSD is to resolve spontaneously by toilet training age; it is unlikely to persist throughout childhood. Until more data are available, it is best to reserve the designation of irritable bowel syndrome for adults, in whom the diagnostic criteria are better outlined.
Diarrhea in patients with CNSD tends to resolve with hospitalization, restriction to three meals per day, or the addition of bulk-forming agents to the diet. Almost any dietary alteration may produce resolution of diarrhea for a short period of time. This makes almost impossible the distinction of CNSD from food allergy on the basis of response to outpatient dietary changes. Outpatient elimination diets are not recommended because they only confuse the parents, and unless carefully controlled, often lead to malnutrition by inadvertent caloric deprivation.
* Milk or protein sensitivity. True maiabsorptive diarrhea in infancy may result from protein sensitivity. As with protein sensitivity in the younger age group, the enteropathy may vary from the gradual development of loose stools to acute enterocolitis with generalized malabsorption. In children who present after 12 months of age, protein-losing enteropathy, peripheral eosinophilia, and iron deficiency anemia may be major manifestations. This diagnosis should be suspected in any child with evidence of colitis in whom no infectious agent can be demonstrated. The diagnosis is made by clinical history, biopsy verification of small bowel and/or colonie mucosal damage, and response to rechallenging with the offending agent. The rechallenge should be done only after the damage to the mucosa has been given a chance to heal. It may be done in the same manner as that suggested for the younger child. Biopsy of the small bowel or colon may be done to confirm the damage, but this is not necessary if good evidence is demonstrated by careful stool testing - either two stools with a pH less than 6.0 and Clinitest greater than 0.5 percent as evidence for malabsorption, or two successively passed stools with blood or white cells as evidence of mucosal damage.
In the rare case where differentiation cannot be made the treatment of protein sensitivity is the same as in the younger age group. Milk and soy protein sensitivity usually does not persist after two years of age. A tolerance test should be repeated at this age and usually restriction can be removed. It is inaccurate to refer to milk and soy protein sensitivity as an allergy. As yet, the immunologie mechanisms constituting an allergy have not been confirmed for milk or soy protein. It seems reasonable to suspect that other dietary proteins may also produce mucosal damage, but this, as well, remains to be documented.
* Celiac disease. Celiac disease is relatively more rare in the United States than it is in Europe or Canada. The mechanism of inheritance of celiac disease is unknown, although ten percent of first and second degree family members may show the disease on biopsy, even if they lack the clinical symptoms. It is caused by a congenital inability to tolerate a protein - gluten - found in wheat, barley, rye, and oats. Typically the disease becomes manifest between one and three years of age, with stools of gradually increasing frequency, looseness, paleness, and bulk. First the child's weight, and then height, deviate from the progression customary on growth grids. The child's abdomen often distends massively as bulk is lost from the extremities. He characteristically becomes lethargic and irritable to the point of inconsolabilily. The child may fail to progress to developmental milestones. Symptoms of calcium deficiency, loss of bone mass, bleeding tendency, and unexplained iron deficiency anemia may also be presentations of celiac disease in childhood.
The diagnosis of celiac disease requires demonstration of absence of villi in the proximal jejunum. An indistinguishable histologie picture may be seen with infectious gastroenteritis or following milk and soy protein intolerance. However, severely flattened biopsies with these conditions are usually seen in infants less than four months of age, prior to the time the gluten exposure usually occurs.
Children with celiac disease almost always respond to a gluten-free diet within one or two weeks. Full healing of the mucosa typically takes three to six months. The response to a gluten-free diet following demonstration of severe mucosal injury is diagnostic. In the rare circumstance where the distinction cannot be made between gluten sensitivity and infectious or milk/ soy protein-induced mucosal injury, the patient may require rebiopsy and rechallenge.
* Giardiasis. Giardiasis is the most common cause of parasite-induced malabsorption in North America. The motile organism is present in asymptomatic infants and is transmitted through contact with contaminated feces, food, or water. Children at any age may present with acute gastroenteritis and the infection may persist, resulting in malabsorption similar to that seen with celiac sprue. The diagnosis depends on finding parasites in the stool, duodenal aspirate, or small bowel biopsy. Stool examination is notoriously inaccurate and is positive in only 40 percent of cases. Duodenal aspirate, small bowel biopsy, and the string test are much more reliable, yielding a positive diagnosis in 90 percent of the cases. The drug of choice at this time is either Atabrine®, for five to seven days, or metronidazole for a similar length of time.
* Congenital sucrase-lsomaltase deficiency. While rare, this is the most common hereditary disaccharidase deficiency. It may only become manifest when the patient is exposed to sufficient sucrose to result in malabsorption. This rarely occurs early in infancy, unless soy protein formula or fruits and vegetables constitute the major dietary intake. With increasing age, exposure to sucrose and isomallose increases, and watery diarrhea results - occasionally with dehydration but often without failure to thrive. Stools are acidic; since sucrose is not a reducing sugar, stools will show the presence of reducing substances only after acid hydrolysis. Diagnosis may be suggested by a flat oral sucrose tolerance test with the appearance of sugar in the stools. Confirmation is achieved by demonstrating a pathologically decreased sucraseisomaltase level with normal lactase levels and a small bowel biopsy with normal villous architecture.
* Three to 18 years of age. After toilet training is achieved, usually by age three, chronic diarrhea is much less likely to be a pediatrie complaint. This is because whatever causes CNSD is no longer a problem. Irritable bowel syndrome, if it exists in childhood at all, is distinctly unusual and the diagnosis in this age group must always be considered suspect. Celiac sprue can be present at any age. If it presents later in the first decade of life, celiac sprue may manifest only by the failure to gain weight and grow. Delayed progress through puberty is often the initial manifestation of this condition. Youngsters who have failure of pubertal progression should be carefully screened for signs of malabsorption and malnutrition. If any are seen, small intestinal biopsy should be done in order to look for evidence of the disease.
* Crohn's disease. Another cause of malabsorption and diarrhea during ages four to 1 8 years is Crohn's disease. The most common presentation of Crohn's disease is abdominal pain, fever, and diarrhea. Malabsorption may occur in only a small number of patients who have this illness. However, there are youngsters with Crohn's disease with extensive involvement of the jejunum as well as the ileum, who may present with the diarrheal syndrome associated with malabsorption. These youngsters typically have histories of low-grade fever ranging from 380C to 390C. This may be associated with crampy periumbilical or right lower quadrant pain following meals. Some younsters with Crohn's disease may have malabsorption but deny pain. Any youngster with a history of intermittent or lowgrade fevers with elevated sedimentation rate should be suspected of having Crohn's disease. Upper gastrointestinal series and a barium enema with proctosigmoidoscopy and biopsy should be considered. Radiographie studies will often revéala characteristic lesion in this disease that consists of loss of mucosal patterns, strictures, or fistula. In the colon, the lesions may show characteristic skip areas. Biopsies may show granulomas and giant cells in the tissue of both the small intestine and colon.
Treatment of Crohn's disease depends, in part, on the degree of involvement in the intestine and the delay in puberty. Intermittent low-dose cortîcosteroids or parenteral nutrition should be considered in patients with severe growth failure. Those who show obstructive symptoms should be considered for resection. Growth acceleration in Crohn's disease will not occur if diseased bowel is in place or if surgery is done while the patient is pubertal.
* Ulcerative colitis. This common cause of chronic diarrhea after age four is characterized by bloodstreaked stools with increasing frequency or bloody mucoid diarrhea. These youngsters are similar in many ways to those with Crohn's disease, in that they may have fever and extraintestinal symptoms of arthritis, iritis, or skin lesions. Proctosigmoidoscopy and rectal biopsies should always be done in these patients and specimens taken to exclude amoebiasis and bacterial-induced colitis. Barium enema should only be done in those who are not severely ill and toxic. Treatment comprises corticosteroids and salicyloazosulfapyridene, depending on the severity of the symptoms. Surgery is required for those who are refractory to medical treatment or fail to gain weight and grow for one year.
Ameni ME. Inflammation disease of lhe colon and ulcerai iv e colitis and Crohn's colitis. J Pediatr 86: 322, 1975.
Anderson CM, Gracey M, Burke Y, Celiac disease: Some siili controversial aspects. Arch Dis Child 47:292, 1972.
Hofmann AF. Hat absorption and malabsorption: Physiology, diagnosis, and treatment, Viewpoints Digestive Dis 9:4, 1977.
Kopel KB. Ciasiroimeslinal manifestation of cystic fibrosis, Gasiroenterology 62:483, 1972.
Phillips SK. Diarrhea: A broad perspective. Viewpoints Digestive Dis 7:5, 1975.
Nelson WE. Textbook of Pediatrics, 11th ed. Philadelphia. Saunders. 1979. pp 1075-89.