The term "diarrhea" refers to an increase in the frequency, fluidity or volume of bowel movements, relative to the usual habit of an individual.[1-3] This bowel problem may be considered chronic if it persists for 14 or more days.
Chronic diarrhea in children is a common problem with numerous causes. Although most of these causes are benign, serious illnesses may present as chronic diarrhea. This article reviews the etiology of chronic diarrhea and outlines an approach to the investigation of this problem.
Causes and Clinical Manifestations
The causes of chronic diarrhea in children are listed in Table 1.
Gastrointestinal infection is by far the most common cause of chronic diarrhea in children. The major bacterial pathogens include enteropathogenic and enterohemorrhagic Escherichia coli, Salmonella species, Shigella species, Yersinia enterocolitica and Campylobacter jejuni. Major parasitic causes of chronic diarrhea include Giardia lamblia, Entamoeba histolytica and Cryptosporidium species. Common viral agents include rotavirus, adenovirus, Norwalk virus and the enteroviruses.
Acute infectious gastroenteritis may be complicated by postenteritis diarrhea occurring after damage to the small intestinal mucosa, with resulting secondary disaccharidase deficiency and carbohydrate intolerance. Typically, patients with postenteritis diarrhea relapse with diarrhea when lactose-containing foods are reintroduced into the diet. In infants and young children, systemic infections, such as a urinary tract infection, may occasionally be associated with chronic diarrhea.
INTOLERANCE TO PROTEIN
Protein intolerance, especially to cow's milk or soy protein, is a common cause of chronic diarrhea. Symptoms usually occur before six months of age. Associated manifestations include bloody diarrhea, anemia, protein-losing enteropathy and extraintestinal manifestations of allergy, such as eczema, hives or asthma.
CHRONIC NONSPECIFIC DIARRHEA
Chronic nonspecific diarrhea of childhood is one of the most common causes of chronic diarrhea. This benign, self-limited disorder usually presents in children between the ages of six months and three years.8,9 The male to female ratio is 2:1.
The syndrome is characterized by persistent or recurrent episodes of voluminous loose stools, usually with six or more stools per day. Undigested food particles may be noted in the stools. Nocturnal diarrhea is absent. Despite having diarrhea, children with this disorder thrive and appear healthy.
The exact etiology of chronic nonspecific diarrhea of childhood is not clear. The syndrome may occur after a viral infection or the institution of dietary restrictions, such as the elimination of milk and dairy products. In one study, the mouth-to-anus transit time of food in children with chronic nonspecific diarrhea was found to be shorter than in age-matched control subjects. Emotional stress and excessive ingestion of cold or hyperosmolar fluid (fruit juice) have also been implicated as possible causative factors.[8,9]
Excessive intake of fluids, especially hyperosmolar fruit juice, may cause chronic diarrhea.[10,11] Osmotic diarrhea can be caused by common dietary sugars such as sorbitol and fructose. Sorbitol is found in significant concentrations in prunes, pears, peaches, apple juice and sugar-free gum. Fructose is found in honey, dried figs, dried dates, prunes and some soft drinks. In children with diarrhea resulting from excess hyperosmolar fluid intake, the first stools of the day are usually formed.
Primary deficiencies of disaccharidase (i.e., lactase, sucrase or isomaltase) are rare. However, secondary disaccharidase deficiencies are common, and they are associated with other gastrointestinal disorders, including infection, bacterial over-growth and untreated celiac disease.
Diarrhea caused by carbohydrate loss may be the result of osmotic or fermentative mechanisms. In fermentation, malabsorbed sugars are broken down by colonic bacteria into osmotically active organic acids with associated hydrogen production.
Typically, diarrhea resulting from disaccharidase deficiency is explosive and watery. Other symptoms include abdominal pain, bloating and flatulence.
Primary monosaccharide malabsorption is rare and is inherited as an autosomal recessive trait. The characteristic defect is an impairment in the ability of cells in the intestinal mucosa to actively transport glucose and galactose, so that only about 10 percent of the ingested glucose and galactose can be absorbed. This absorption disorder, which usually presents in neonates, is characterized by watery diarrhea with an acidic stool.
Celiac disease is associated with villous atrophy of the proximal small intestine. This condition is the result of a permanent intolerance to the gliadin fraction of gluten protein. Celiac disease has a strong association with histocompatibihty-type human leukocyte antigens (HLAs), such as HLA-B8 and class II HLA-DR3, HLA-DR7, HLA-DQ, HLA-W2 and HLA-DR4.[7,14]
Symptoms can develop any time after gluten (e.g., wheat, barley, rye) is introduced into the diet. Most children with celiac disease present at six to 24 months of age. Major manifestations include chronic diarrhea, anorexia, failure to thrive, muscle wasting, irritability and abdominal distention. Characteristically, the stools are pale, loose, bulky and oily, and they have a pungent odor.
Cystic fibrosis, the most common pancreatic disorder causing chronic diarrhea, is inherited as an autosomal recessive trait. The gene responsible for cystic fibrosis has been localized to the long arm of chromosome 7.
The triad of pancreatic exocrine deficiency, chronic obstructive pulmonary disease and an abnormally high level of chloride in the sweat is present in most patients. Clinically, the disease may manifest as steatorrhea (fat-containing stools) with malabsorption, meconium inspissation in the neonatal period, prolonged neonatal jaundice, growth retardation, anasarca, recurrent or chronic chest infections, nasal polyps, rectal prolapse or digital clubbing. Even though they have voracious appetites, most children with cystic fibrosis remain malnourished.
Shwachman-Diamond syndrome is characterized by neutropenia and pancreatic insufficiency. Other features include short stature and skeletal abnormalities. The disease is usually inherited as an autosomal recessive trait, but an autosomal dominant mode of inheritance has also been reported. Shwachman-diamond syndrome may be differentiated from cystic fibrosis by the presence of normal levels of sweat chloride and the absence of pulmonary disease.
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease frequently develops in late childhood or during adolescence. This disorder is characterized by unpredictable remissions and exacerbations. The etiology of inflammatory bowel disease is unknown, but genetic factors appear to make persons with this disorder more vulnerable to an immunologically related inflammatory reaction.
Ulcerative colitis is an inflammatory disease that most commonly involves the mucosa of the colon and rectum. Predominant symptoms include bloody diarrhea, lower abdominal cramps and tenesmus. Anorexia, malaise, weight loss and growth failure occur as the disease progresses. Older children may have extraintestinal manifestations, including arthritis, erythema nodosum, pyoderma gangrenosum, iritis, hepatitis, digital clubbing and intermittent fever.
Crohn's disease is a segmental transmural inflammatory disease that may affect one or more segments of the gastrointestinal tract, from the mouth to the anus. The distal ileum and colon are the bowel segments most commonly affected. The classic symptom triad includes bloody diarrhea, abdominal pain and weight loss. Stomatitis and chronic perianal lesions, such as fissures, fistulas and abscesses, may be present bullous and eczematous lesions symmetrically distributed in the perioral, acral and perineal areas.
In children with intestinal lymphangiectasia, rupture of the intestinal mucosal lacteals may result in massive gastrointestinal loss of fat and protein. Consequently, lymph may leak into the bowel lumen. Children with this condition typically have steatorrhea, protein-losing enteropathy, anemia, malnutrition and growth retardation.
Abetalipoproteinemia is a disorder resulting from the inability to form chylomicrons in the intestinal mucosa. Typically, children with this rare autosomal recessive disorder present with diarrhea, failure to thrive, acanthocytosis, retinitis pigmentosa and cerebellar ataxia.
CONGENITAL CHLORIDE-LOSING DIARRHEA
Chronic diarrhea may occur because of the absence of a normal ileal mechanism for active absorption of chloride in exchange for bicarbonate. Typically, this congenital problem presents in neonates and is characterized by watery diarrhea and metabolic alkalosis.
A thorough history (Table 2) and a complete physical examination (Table 3) are important in the evaluation of chronic diarrhea.
Certain basic laboratory studies can be helpful in many patients with chronic diarrhea. The stool should be analyzed for pH, reducing substances, occult blood, fatty acid crystals, fat globules, red blood cells, white blood cells, and ova and parasites. The stool culture may also yield important information. Other potentially useful tests include a complete blood count with differential and peripheral smear, an erythrocyte sedimentation rate, serum electrolyte concentrations, total protein and albumin levels, and a serum carotene level.
The presence of reducing substances in a stool with a pH less than 6 suggests carbohydrate malabsorption. A positive stool guaiac test indicates intestinal mucosal breakdown, which may be caused by gastrointestinal infection, protein intolerance or inflammatory bowel disease. The guaiac test may also be positive if the diet contains meat.
Fat globules in the stool may be normal in the first few months of life.[7,22] In an older child, the presence of fat globules suggests steatorrhea. Lubricants used during a digital examination to obtain a stool specimen may give a false-positive result for stool fat. Refractile fatty-acid crystals suggest a mucosal problem such as celiac disease.
A fresh stool sample should be examined microscopically. The presence of a large number of neutrophils or red blood cells indicates bacterial gastroenteritis or inflammatory bowel disease. The presence of eosinophils suggests protein intolerance or parasitic infestation. Mobile parasites (G. lamblia or E. histolytica), cysts (protozoa or nematodes) and ova (nematodes and trematodes) may be seen. Stool cultures for specific organisms should also be performed.
A complete blood count is often helpful. Neutrophilia and an increased number of band forms or toxic granulations are suggestive of bacterial infection. Neutropenia may be present in some immunodeficiency disorders, while eosinophilia may occur in parasitic infestation or protein intolerance. Hypochromic microcytic anemia suggests chronic gastrointestinal blood loss or malabsorption of iron. Acanthocytes in the peripheral smear suggest abetalipoproteinemia, while macrocytosis suggests vitamin [B.sub.12] or folate deficiency. An elevated erythrocyte sedimentation rate suggests active infection or inflammatory bowel disease.
In malnutrition, the serum albumin and globulin levels are decreased proportionally In contrast, protein-losing enteropathy is characterized by a greater loss of albumin and therefore a disproportionately depressed serum albumin level. The serum carotene level is an inexpensive and simple marker for fat malabsorption, assuming dietary carotene intake is adequate.
In watery diarrhea, calculation of the stool osmotic gap may help to differentiate diarrhea caused by osmotic agents such as sugars from diarrhea caused by abnormalities in the ionic transport of electrolytes. The stool osmotic gap is calculated by the following formula: stool osmolality - [2 x (stool sodium + stool potassium)]. If the stool osmotic gap is increased, the diarrhea may be caused by an osmotically active agent, such as a sugar. If there is no osmolar gap, the diarrhea is more likely the result of impairment of the ionic transport of an electrolyte, which is common in infectious gastroenteritis, bile salt malabsorption, bacterial overgrowth, laxative abuse and short-bowel syndrome. Other tests that should be performed when indicated include serum immunoglobulin levels for immunodeficiency, a hydrogen breath test for carbohydrate malabsorption, a 72-hour fecal fat test for fat malabsorption, a sweat chloride test for cystic fibrosis, an upper gastrointestinal series with small-bowel follow-through for anatomic abnormalities and Crohn's disease, a barium enema for Hirschsprung's disease and inflammatory bowel disease, sigmoidoscopy for inflammatory bowel disease and pseudomembranous colitis, a stool assay for giardiasis and a jejunal biopsy for celiac disease.
The authors thank Kathy Campbell-Brown and Paula Pang for their excellent secretarial assistance and Sulakhan Chopra of the University of Calgary medical library for his assistance in the preparation of the manuscript.
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