Chronic Diarrhea
Brad Pasternak, MD
Ashish Chogle, MD
Kristy VanDervoort, BS (MD in 2009)
SUNY-Downstate Medical Center
Zvi Weizman, MD
Ben Gurion University Medical Center
Beer Sheva, Israel
Pre-test (detailed explanations at the bottom):
Q1. True or False. The most significant cow's milk allergen transferred in breast milk is bovine secretory IgA.
Q2. True or False. It is very rare to diagnose cow's milk allergy in children older than 3 years of age.
Q3. Best answer. The best formula for an infant with prolonged bloody diarrhea, failure to thrive, rash, and respiratory wheezing is:
a. Soy-bean formula
b. Amino-acid based formula
c. Goat's milk
d. Casein hydrolyzate
Q4. Best answer. A previously healthy 2-month old infant with a 3 week duration diarrhea is switched from a cow's milk based regular formula to a soy-bean based formula due to persistence of watery stools positive for reducing substances. There is no improvement. The reason for the persistence of his symptoms is most probably:
a. Lactose intolerance
b. Glucose-galactose malabsorption
c. Sucrose intolerance
d. Overfeeding
Q5. Best answer. The most common form of persistent diarrhea in the first three years of life is:
a. Lactose intolerance
b. Milk Protein allergy
c. Toddler's diarrhea
d. Overfeeding
Learning Objectives
At the conclusion of this module, residents will be able to:
1. Recognize the differential diagnosis of chronic diarrhea in infancy.
2. Develop a practical work-up protocol in these cases.
3. Gain an understanding of the various clinical forms of cow's milk allergy in infancy.
4. Recognize the traps of failure to feed and elimination diets leading to Failure to Thrive.
5. Appreciate the consequences and interactions of malnutrition and chronic diarrhea
FACILITATORS PREPARATION:
The material presented here was originally developed for Weizman Z. (1988), Chronic Diarrhea in Solving Common Pediatric Problems: An Algorithm Approach. Editor Margolis CZ. The Solomon Press, New York. pp 165-171.
A readily available overview can be found in Baldassano RN, Liacouras CA. Chronic diarrhea: a practical approach. Pediatr Clin N A 1991; 38: 667-68.
A seminal work showing the deleterious effects of elimination diets is Lloyd-Still JD. Chronic diarrhea of childhood and the misuse of elimination diets. J Pediatr 1979; 95: 10-13.
The modules in the Teacher's Guide on acute diarrhea, celiac disease, and probiotics provide more specific perspectives on diarrheal illness. [Hyperlinks]
INTRODUCTION
The daily stool volume in adults ranges from 100 to 200 grams while children excrete about 5-10 grams per kg. Nearly 65-85% of this stool mass consists of water. Most of the ingested and secreted (saliva, stomach, bile, pancreas) water is absorbed in the small intestine. Even small increases in stool water are sufficient to influence consistency and frequency of bowel movements.
It is duration that distinguishes acute from chronic diarrhea. This material is written for an appreciation of diarrheal diseases lasting 2 weeks or more, the definition of chronicity.
Diarrhea can be subdivided by its physiological mechanism or its etiology. Mechanistically, diarrhea may be a) secretory or b) osmotic [see Probiotics module PIV S6-B].
a) Secretory diarrhea may result from infectious causes or inflammation and is characterized by watery stools with a relatively high electrolyte count that persists even during fasting. The most commonly cited example, though extreme and rare in the developed world, is cholera, which results in a severe secretory diarrhea marked by huge volumes of watery stools. In the developed world, a more common cause of secretory diarrhea is inflammatory bowel disease.
b) Osmotic diarrhea most commonly results from malabsorption, dietary intake, or intestinal injury and is characterized by stools that have relatively low electrolyte content. Osmotic diarrhea tends to resolve when oral intake is eliminated. Diarrhea may also be classified as to etiology: whether it is infectious or non-infectious, or inflammatory or non-inflammatory.
TABLE 1. Osmotic Vs. Secretory Diarrhea
Osmotic Secretory
Stool Volume <200 mL/day >200 mL/day
Response to Fast Stops Diarrhea No Change
Stool Na <70 mEq/L >70 mEq/L
Reducing Substance Positive Negative
Stool pH <5 >6
CAPTION: The origins of the two types of diarrhea are distinct, and thus, so are the treatments. Failure to distinguish means failure to treat effectively.
Concomitant to the osmotic and/or secretory mechanism responsible for diarrheal disease, "dysmotility" is a common occurrence. Here absorptive ability is retained in the face of a rapid transit time and inflammatory diarrhea. It is possible that all three conditions - hyperosmosis, excess secretions, and dysmotility -- are incorporated in a common pathophysiology of chronic diarrhea.
Until about fifty years ago diarrheal diseases were the major cause of infant mortality. In the United States, "Cholera Infantum" was associated with staggering mortality, as described in the 18th century. This disease occurred mainly in bottle-fed infants with a fatal outcome in about 80% of patients. Diarrheal disorders are still the main cause of morbidity and mortality worldwide, especially in developing countries. It is estimated that nearly 3 to 5 billion cases occur every year. The highest prevalence is in children less than five years of age with nearly 500 million diarrhea episodes and about 5 to 18 million fatal cases per year. Children under 3 years of age in such areas may experience as many as 10 episodes of diarrhea yearly.
Most episodes of diarrhea are of relatively short duration, but some may become chronic or persistent. Persistent diarrhea has been defined by the World Health Organization as "diarrheal episodes of presumed infectious etiology that begin acutely but last at least 14 days". We use the terms persistent and chronic synonymously.
Studies in developing countries such as in Asia, Africa, and Latin America have shown that 3-20% of acute diarrheal episodes in children less than 5 years of age become chronic or persistent. Episodes of persistent diarrhea are often associated with deterioration in nutritional status and a substantial risk of death. Even in industrialized countries, mortality of infants hospitalized for diarrhea still exceeds 1%, about half of these from complications of chronic diarrhea.
Case Study
Andrew is a healthy 2 month old infant with a normal perinatal history. He is the product of the first pregnancy of a healthy 24-year old mother with atopic eczema in infancy and asthma in adolescence. Her husband is 31 years old with familial hypertriglyceridemia. Andrew is exclusively breast-fed and is thriving. Four weeks prior to his referral he became very irritable with "gas" and was diagnosed as having bad infantile colic. Over the last 3 weeks he is having irregular stools with bouts of watery diarrhea. Sometimes bloody spots were noticed in his stools. There was no fever and no vomiting. Although his mom is not a strict vegetarian her diet consists mainly of a lot of vegetables, fruits, and dairy products. Andrew's dad smokes about 15 cigarettes a day and had a bad flu with fever and stomach pain a few weeks ago.
Q1. What are important factors to consider in the history and physical exam in a patient experiencing diarrhea?
A1. The extent of the diarrhea must be elicited by asking about frequency, volume, and duration of diarrhea, as well as relation to feeds and specific diet. In addition, travel history, sick-contact exposure, and family history will be helpful.
The physical exam should begin by identifying the child's growth parameters and determining if the diarrhea is associated with failure to thrive. Following this, signs of dehydration and nutrient deficiencies must be looked for. Every child must undergo a rectal examination.
Q2. What is the differential diagnosis for chronic diarrhea in infancy?
A2. There is a wide spectrum of causes for chronic diarrhea in infancy. Some causes are of a benign and self-limited nature that affect the child's health only to a limited extent with no effect on growth rate. On the other hand there are the severe etiologies with major disturbances of normal health resulting in growth failure and poor clinical outcome. A list of most major etiologies for chronic diarrhea is given below. The teacher should discuss each group of etiologies and focus on the most common ones.
TABLE 2.
A. Infection
- Bacterial (Shigella, Salmonella, E. Coli, Campylobacter, Yersinia,
Aeromonas, M. Tuberculosis)
- Viral (Rotavirus, Astrovirus, Norwalk agent, adenovirus,
enteroviruses, CMV)
- Parasitic (Giardiasis, Amebiasis, Strongylodiasis, Cryptosporidiosis)
- Post-infectious diarrhea
- Bacterial overgrowth (blind-loop and stasis syndromes, immune
defects, antibiotics, Clostridium Difficile)
CAPTION: One characteristic of these conditions is that they usually affect more than one person or occur in settings where diarrheal disease is common (e.g., day care, in post surgical situations, etc).
B. Food Allergy
- Cow's milk protein intolerance
- Soy protein intolerance
- Specific food allergy
CAPTION: These conditions rarely occur in isolation from one another.
C. Dietary Causes
- Undernutrition
- Hyperosmotic beverages (natural juices, sorbitol, fructose)
- Overfeeding
- Food intolerance (MSG, nitrates)
CAPTION: The risk for these conditions is suggested by history and physical examination [see module on Assessing Nutritional Status].
D. Intestinal Mucosal Defects
- Celiac disease
- Congenital villous atrophy
- Carbohydrate malabsorption (lactase deficiency, glucose-galactose malabsorption, sucrase-isomaltase deficiency).
- Intestinal lymphangiectasia
- Abetalipoproteinemia
- Acrodermatitis enteropathica
- Congenital chloride diarrhea
- Congenital Na+ diarrhea
- Wolman disease
CAPTION: Failure to thrive is almost always a concomitant finding.
E. Drug-induced
- Laxative overuse
- Antibiotics
- Magnesium salts (antacids)
- Phenolphthalein
CAPTION: Always look for iatrogenic causes. Some medications are taken without consultation, e.g., folk/herbal remedies.
F. Pancreatic Disorders
- Cystic fibrosis
- Schwachman-Diamond syndrome
- Specific enzyme deficiency
CAPTION: A sweat test and evaluation for pancreatic diseases are essential in chronic diarrhea.
G. Biliary Diseases
- Cholestatic liver disease (e.g., biliary cirrhosis)
- Extra-hepatic obstruction (biliary atresia, choledochal cyst)
- Bile-acid malabsorption
CAPTION: Always check stool color, liver function tests, and urine for bile or bile by products.
H. Anatomic Abnormalities
- short-bowel syndromes
- Blind-loop syndromes (malrotation, volvulus, etc.)
CAPTION: Combinations of pain and abdominal surgery are likely with anatomic abnormalities.
I. Inflammatory Bowel Disease
- Crohn disease [not possessive unless Crohn had the disorder]
- Ulcerative colitis
- Eosinophilic gastroenteritis
CAPTION: The conditions are usually associated with pain upon eating (Crohn disease) that is not necessarily associated with stooling. Bloody diarrhea may be present.
J. Motility Disorders
- Hirschsprung's disease
- Chronic constipation
- Pseudo-obstruction syndromes
CAPTION: A rectal exam is essential. Liquid stooling around an obstruction is a common finding in these disorders.
K. Idiopathic
- Chronic non-specific diarrhea of childhood
- Intractable diarrhea of infancy
CAPTION: Essentially, these are diagnoses that are left when a firm diagnosis is not possible. Never make these diagnoses in a child with failure to thrive. It is always something even if you can't identify!!
L. Miscellaneous
- Immune (IgA deficiency, AIDS, SCID, agammaglobulinemia etc.)
- Secreting tumors (gastrin, VIP, somatostatin etc.)
- Endocrine (hypoparathyroidism, hyperthyroidism, adrenal etc.)
- Infiltrating malignancy (lymphoma, leukemia)
- Extra-intestinal occult infection
- Factitious
CAPTION: "Lumpers" vrs. "Splitters." As with all attempts to create seprate categories to assay a large domain such as chronic diarrhea, the attempt fails when complete conformity is expected. The miscellany above shows the outliers.
Nevertheless, it is better to develop and overarching schema that serves to distinguish basic differences. Without this approach no understanding and thus no comprehensive system for diagnosis and treatment is possible.
Q3. What is the most common form of persistent diarrhea in the first 3 years of life?
A3. The most typical entity is called "Toddler's diarrhea" (Chronic non-specific diarrhea of childhood), and this the most likely diagnosis for Andrew. Note that he is clinically well with normal absorptive ability, but he is having increased numbers of loose stools each day. They are brown and watery, often containing undigested stool particles.
The cause is a result of dietary intake of a high amount of fruit juice with considerable amounts of non-absorbable solutes and sorbitol (also poorly absorbed). If a child is drinking >150 mL/kg/day of fluid, this should be restricted to no more than 90 mL/kg/day with a maximum of 8oz of juice each day. This will resolve the diarrhea over a few days.
Q3. What are the criteria for "intractable diarrhea syndrome"?
A3. Infants less than 3 months of age, diarrhea for more than 14 days duration, failure to thrive, and 3 or more negative stools for cultures and ova and parasites.
Lo and co-workers describe the most common causes for intractable diarrhea are post-infectious, Giardiasis, cow milk allergy, and celiac syndrome. (See Lo, et al. Pediatrics 1983;72:795-80.) These should be looked for when any of the four conditions listed above are identified in a child with chronic diarrhea.
Q4. How is Chronic Diarrhea evaluated?
A4. The following algorithm presents a practical guide towards making a useful differential diagnosis, along with the above three parameters.
FIGURE 1. An Algorithm for assessing cause of chronic diarrhea in childhood.
Derived from Weizman Z, Chronic Diarrhea in Solving Common Pediatric Problems: An Algorithm Approach. Editor Margolis CZ. The Solomon Press, New York, 1988. pp 165-169. This algorithm is based on a community-based approach and is very simple to use.
The most important examination in chronic diarrhea is the stool sample!
- A microscopic examination will identify inflammatory conditions, as these may present with occult blood and PMNs.
- Testing the stool for reducing substances helps diagnose carbohydrate malabsorption. This test though, does not detect sucrose-isomaltase deficiency because sucrose is not a reducing sugar. A stool pH between 5.0 and 6.0 might give a clue. Another screening method is to use the Clinitest tables in stool, whose sucrose is hydrolyzed by boiling with 0.1 N HCL Additional methods are an oral sucrose load test with blood sampling for glucose or a breath hydrogen test. However, the most reliable way is to to perform a specific enzyme assay on an intestinal biopsy specimen.].
- Electrolytes and osmolality assays will determine if this is a secretory diarrhea.
- The stool should be cultured to find if there are enteric pathogens present.
- If weight loss exists, a 72-hour fecal fat analysis is warranted to determine if steatorrhea or malabsorption is present.
- A fecal fat test is necessary for all children with diarrhea and growth failure. Fecal elastase testing is becoming available also.
A separate evaluation for cystic fibrosis would include a sweat chloride test or fecal elastase assay.
Q5. What other test can be used to detect carbohydrate malabsorption?
A5. The hydrogen breath test is a noninvasive and non-expensive test that uses the fermentation product of hydrogen produced by enteric flora's action on carbohydrates. This is performed after an oral carbohydrate load such as lactose or sucrose (or even glucose) to evaluate for bacterial overgrowth.
Q6. What blood tests should be ordered in a patient with chronic diarrhea?
A6. The specific tests are determined by the clinical situation and suspicion for nutrient deficiencies, malnutrition, and inflammatory disease.
-A CBC will address possible anemia and status of iron, B12 and folate.
-A platelet count acts as an acute phase reactant and may give evidence of an inflammatory condition of Vitamin E deficiency.
-Serum levels of 25-OH Vitamin D indicate fat malabsorption. Always assess calcium, phosphorus, and alkaline phosphatase.
-Serum Immunoglobulins are also important to assess in children with failure to thrive and diarrhea, with emphasis on IgA.
As shown in our evaluation, Andrew's most likely diagnosis is cow milk allergy, induced by bovine allergens secreted in his mothers' breast milk following ingestion of bovine proteins.
Q7. What are the clinical forms of cow's milk allergy in infancy, and does this entity exists in exclusively breast-fed infants?
A7. Cow's milk allergy develops in early infancy and rarely after 12 months of age. The onset of symptoms is in most cases is closely related to the time of introduction of a cow's milk based formula.
A broad spectrum of symptoms and signs may be attributed to ingestion of cow's milk. Most reactions are localized to the gastrointestinal tract (vomiting, diarrhea, colic), but may also cause systemic symptoms such as anaphylaxis, skin rash, and respiratory phenomena. The typical IgE-mediated symptoms may occur within a few minutes, but other delayed-type reactions may occur after days.
Exclusively breast-fed infants may react to cow's milk proteins (mainly beta-lactoglobulin) ingested by the mother and transferred to the infant via the breast milk. It is quite common in these cases to find blood-streaked diarrhea due to a mild colitis. Stool smear may reveal many leukocytes.
TABLE 3. Clinical Spectrum of Milk-Protein Allergy
Gastrointestinal Manifestations of IgE Mediated Effects:
- Gastrointestinal Bleeding
- Eosinophilic Gastroenteritis
- Diarrhea and Abdominal Pain
- Allergic Colitis
- Protein-Losing Enteropathy
- Gastroesophageal Reflux Disease
- Infantile Colic
- Persistent Constipation
Extra-intestinal Manifestations of IgE Mediated Effects:
- Acute Urticaria
- Angioedema
- Iron Deficiency Anemia
- Rhinitis
- Wheezing
- Otitis Media
- Eczema
- Failure to Thrive
Non-IgE Mediated Effects:
- Food-Induced Enterocolitis Syndrome
- Food-Induced Eosinophilic Colitis
- Food-Induced Enteropathy
CAPTION: Cow milk allergy has broad impact on both intestinal function and overall children's nutrition. See module on food allergy for further discussion.
Q8. What is the most practical and cost-effective treatment plan for cow's milk allergy?
A8. In breast-fed infants, the mother should avoid dairy products, and in some resistant cases, also soy and egg proteins. Formula-fed infants with mild symptoms may benefit from switching to a soy-based formula. Mothers often make that switch on their own, but cross-allergies to cow milk are common. It is now suggested to go directly to casein hydrolysate formula.
Some infants with severe cow's milk allergy also develop lactose intolerance. No soy based formulas contain lactose, but some contain sucrose which may cause ongoing diarrhea due to sucrose intolerance. Therefore, it is necessary to check the product label. In infants with major symptoms such as anaphylaxis, wheezing, failure to thrive, recurrent vomiting, prolonged diarrhea, etc., a casein hydrolysate is indicated.
When severe damage to the intestines with malabsorption is suspected, a medium-chain triglyceride (MCT) enriched hydrolysate is preferred. In rare cases where symptoms do not subside following a hydrolysate introduction, an amino acid-based formula is indicated.
References:
American Academy of Pediatrics. (2004) Chronic Diarrheal Disease.
In Kleinman RE (ed) AAP Nutrition Handbook, 5th edition. Elk Grove Village, IL American Academy of Pediatrics. Pg 459- 70.
Baldassano RN, Liacouras CA. Chronic diarrhea: a practical approach. Pediatr Clin N A 1991; 38: 667-686.
Bhutta ZA, Molla AM, Issani Z, Badruddin S, Hendricks K, Snyder JD.
Dietary management of persistent diarrhea. Pediatrics 1991; 88: 1010-1018.
Farrell RJ, Kelly CP. Celiac Sprue. NEJM 2002; 346: 180- 88.
Green PH, Celiac Disease. The Lancet 2003; 362: 383-91.
Lloyd-Still JD. Chronic diarrhea of childhood and the misuse of elimination diets. J Pediatr 1979; 95: 10-13.
Lo CW, Walker WA. Chronic protracted diarrhea of infancy: a nutritional disease. Pediatrics 1983; 72: 786-800.
Scherer SH, No one SA, Koerner CB, Christie L, Burks W, Sampson HA. Hypoallergenicity and efficacy of an amino acid based formula in children with cow's milk and multiple food hypersensitivities. J Pediatr 2001;138:688-93.
Weizman Z. Chronic Diarrhea in Solving Common Pediatric Problems: An Algorithm Approach. Editor Margolis CZ. The Solomon Press, New York, 1988. pp 165-171.
Annotated Pre-Test Answers
A1. False. The correct answer is beta-lactoglobulin.
A2. True. By this age, intestinal mucosa is mature. Those not affected by this age are unlikely to become affected. Some prior affected children can resume drinking milk or consuming dairy products.
A3. B. The other choices including goat milk, soy "milk," and casein derivatives all have cross-reacting proteins that are likely to affect this highly allergic child.
A4. C. The presence of reducing substance suggests a metabolic problem affecting carbohydrate metabolism. The most common problem would be a lactase deficiency with a failure to break the glucose-galactose link. Lactose is not put into soy formula. Thus, sucrase deficiency moves ahead on the differential. Overfeeding does not cause a reducing substance containing diarrhea.
A5. C. Toddlers' diarrhea is caused by excess consumption of absorbable and non-absorbable sugars found in juice beverages.
