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11
Diarrhea
Bhaskar Gurram
Diarrhea is defined as a stool volume of greater than 10 g/kg/day in predominantly diarrheal illness developing within days of exposure
infants and toddlers and greater than 200 g/day in older children. (Fig. 11.1). A recent history of travel suggests traveler’s diarrhea, more
Functionally, diarrhea should be considered if a patient is passing 3 or than 80% of which is caused by bacterial species that are endemic to
more unusually loose stools in a 24-hour period or is passing stools the area of travel, to which the patient has not been previously exposed.
more frequently than usual, with a consistency looser than what is Recent travel may also suggest parasitic or helminthic infection. Expo-
considered normal for that individual. Diarrhea is classified broadly by sure to health care settings suggests nosocomial diarrhea. Patients
the duration of symptoms. Acute diarrhea is usually a self-limited with a history of immunodeficiency or malnourishment may be more
illness that lasts for 2 weeks or less. Chronic diarrhea persists for more likely to have an infection with atypical or opportunistic organisms or
than 2 weeks. The etiologies of acute and chronic diarrhea differ by to have a more protracted and severe course. Hematuria or oliguria
age (Table 11.1). may suggest hemolytic uremic syndrome as a complication of infec-
Diarrhea is further classified by pathophysiology, which typically tion with Escherichia coli 0157 : H7 or Shigella.
involves 1 or more of the following mechanisms: (1) osmotic diar-
rhea, characterized by the presence of an increased intraluminal Physical Examination
osmotic load leading to passive diffusion of fluid into the gastro- Physical examination should focus on assessing the level of hydration
intestinal lumen; (2) secretory diarrhea, characterized by increased and the need for fluid resuscitation (Table 11.6). The general examina-
secretion of fluid into the gastrointestinal lumen beyond the capacity tion may reveal nonenteric infections that could present with diarrhea,
to be reabsorbed; and (3) altered gastrointestinal tract motility. Dif- such as otitis media, pneumonia, or sepsis. Abdominal tenderness or
ferentiating osmotic from secretory diarrhea allows for a more directed masses suggest appendicitis, intussusception, or less commonly, toxic
diagnostic evaluation (Table 11.2). Osmotic diarrhea may be related megacolon. Generalized toxicity or shock may occur with hemolytic
to the malabsorption of carbohydrate, fat, or protein or to the pres- uremic syndrome or with sepsis, such as from invasive Salmonella or
ence of nonabsorbable substances in the gastrointestinal lumen. The staphylococcal toxic shock syndrome.
characteristics of the stool may provide information that allows for
the identification of the malabsorbed substance, particularly for iso- Viral Diarrhea
lated carbohydrate and fat malabsorption (Table 11.3). Secretory Rotavirus infection. Rotavirus is the leading cause of severe diar-
diarrhea is characterized by an excess of crypt cell fluid and electrolyte rhea in infants and young children. The introduction of an effective
secretion that exceeds the absorptive capabilities of the villi and is vaccine has decreased the incidence, with most infections occurring in
classified by the presence or absence of normal villi. Inflammatory unvaccinated children under 3 years of age. Transmission is by the
diarrhea of both infectious and noninfectious etiologies usually fecal-oral route and the incubation period ranges from 1 to 3 days.
involves both osmotic and secretory components. Finally, surgical Patients typically present with the acute onset of fever and vomiting
bowel resection may decrease the surface area available for the resorp- followed 1-2 days later by watery diarrhea. Symptoms generally persist
tion of both fluid and solutes, leading to both a secretory and osmotic for 3-8 days. In moderate to severe cases, dehydration, electrolyte
diarrhea. The causes of diarrhea based on pathophysiology are pre- abnormalities, and acidosis may occur. In immunocompromised
sented in Table 11.4. children, persistent infection and chronic diarrhea can develop, with
persistently positive diagnostic assays. Chronic infection is to be dif-
ACUTE DIARRHEA ferentiated from postinfectious malabsorption seen in some immuno-
competent children, in whom the small intestinal mucosa may require
History 3-8 weeks to recover its absorptive ability. Diagnosis is confirmed by
Acute diarrhea in children is most often infectious (Table 11.5), nucleic acid amplification assays, enzyme immunoassay (EIA), immu-
although it may be secondary to noninfectious inflammatory pro- nochromatography, or latex agglutination assay for group A rotavirus
cesses, toxins, or medications. The etiology of acute diarrhea is sug- antigen detection in the stool.
gested by both the history and characteristics of the stool. Fever or Norovirus infection. Norovirus is a single-stranded RNA virus of
blood in the stool suggests an infectious cause. Watery diarrhea is the Calciviridae family and is the leading cause of epidemic outbreaks
typical of viral gastroenteritis, as well as some bacterial and parasitic of acute gastroenteritis, as well as the most common cause of food-
infections. Dysentery, characterized by severe diarrhea and the pres- borne illness and foodborne disease outbreaks in the United States.
ence of blood and mucus in the stool, suggests bacterial colitis. Vomit- Young children have the highest incidence of infection. Transmission
ing and diarrhea developing within hours of ingesting food suggests is via the fecal-oral route or through contaminated food or water.
exposure to preformed toxins in the food, rather than the acquisition Norovirus gastroenteritis typically presents with the abrupt onset of
of an enteric pathogen from the food, which is characterized by a vomiting accompanied by watery diarrhea, abdominal cramps, nausea,
182
CHAPTER 11 Diarrhea 183
TABLE 11.1 Differential Diagnosis of Acute and Chronic Diarrhea by Age

Infants Children Adolescents
Acute
Common Infectious gastroenteritis Infectious gastroenteritis
Infectious gastroenteritis Food poisoning Food poisoning
Systemic infection Antibiotic-associated diarrhea Antibiotic-associated diarrhea
Medication-induced (e.g., antibiotics, laxatives) Food poisoning Hyperthyroidism
Food protein–induced enterocolitis syndrome (FPIES) Systemic infection
Food poisoning
Overfeeding
Rare
Hirschsprung-associated enterocolitis
Neonatal opioid withdrawal
Chronic
Disorders of Absorption and Transport of Disorders of Absorption and Transport Disorders of Absorption and
Nutrients and Electrolytes of Nutrients and Electrolytes Transport of Nutrients and
Primary lactase deficiency Lactose intolerance Electrolytes
Secondary (e.g., postinfectious) lactase deficiency Secondary (e.g., postinfectious) lactase deficiency Lactose intolerance
Congenital sucrose-isomaltase deficiency Congenital sucrose-isomaltase deficiency Laxative abuse
Congenital chloride diarrhea Primary bile acid diarrhea Disorders of Intestinal Motility
Congenital sodium diarrhea Familial diarrhea syndrome Irritable bowel syndrome
Acrodermatitis enteropathica Disorders of Intestinal Motility Pesudoobstruction and bacterial overgrowth
Glucose-galactose malabsorption Toddler’s diarrhea Infectious Etiologies
Fanconi-Bickel syndrome Irritable bowel syndrome Giardiasis
Lysininuric protein intolerance Infectious Etiologies Cryptosporidium
Chylomicron retention disease Giardiasis Neuro-Enteroendocrine Diarrhea
Abetalipoproteinemia Cryptosporidium Primary adrenal insufficiency
Enterokinase deficiency Defects in Enterocyte Structure Defects in Intestinal Immune-
Maltase-glucoamylase deficiency Trichohepatoenteric syndrome (syndromic diarrhea) Related Homeostasis
Primary bile acid diarrhea Neuro-Enteroendocrine Diarrhea Inflammatory bowel disease
Familial diarrhea syndrome Proprotein convertase 1/3 deficiency Celiac disease
Diarrhea-associated DGAT1 mutation X-linked lissencephaly Eosinophilic gastroenteritis and colitis
Defects in Enterocyte Structure Secretory tumors (e.g., neuroblastoma, VIPoma) Pancreatic Insufficiency
Congenital tufting enteropathy Defects in Intestinal Immune-Related Chronic pancreatitis
Microvillus inclusion disease Homeostasis
Trichohepatoenteric syndrome (syndromic diarrhea) Celiac disease
Neuro-Enteroendocrine Diarrhea Inflammatory bowel disease
Enteric anendocrinosis Eosinophilic gastroenteritis and colitis
Mitchell-Riley syndrome Early-onset enteropathy with colitis
Proprotein convertase 1/3 deficiency XIAP deficiency
X-linked lissencephaly Autoimmune enteropathy
Secretory tumors (e.g., neuroblastoma) Pancreatic Insufficiency
Defects in Intestinal Immune-Related Cystic fibrosis
Homeostasis Chronic pancreatitis
Cow’s milk or soy-milk protein colitis
Eosinophilic gastroenteritis and colitis
Early-onset enteropathy with colitis
IPEX syndrome
IPEX-like disorders
XIAP deficiency
Autoimmune enteropathy
Other primary immune deficiency disorders (e.g., SCID)
Pancreatic Insufficiency
Cystic fibrosis
Shwachman-Diamond syndrome
Johansson-Blizzard syndrome
Pearson syndrome
DGAT1, Diacylglycerol O-acyltransferase 1; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; SCID, severe combined
immunodeficiency; VIP, vasoactive intestinal peptide; XIAP, X-linked inhibitor of apoptosis.
184 Section 3 Gastrointestinal Disorders
and vomiting. Systemic manifestations, including myalgia, fatigue, and Symptoms slowly resolve within 3-5 days, although excretion of the
headache may accompany gastrointestinal symptoms. Diagnosis is organism may persist for several weeks. The organism is readily iso-
confirmed by nucleic acid amplification assays that detect viral RNA lated from culture of the stool or a rectal swab, or may be identified
from the stool. via multiplex polymerase chain reaction (PCR) assays that detect mul-
tiple bacterial, viral, and parasitic enteric pathogens.
Bacterial Diarrhea Shigella infection. Most Shigella infections in the United States
Most bacterial diarrheal illnesses are foodborne and affect infants and occur in young children 1-4 years of age, with a peak seasonal inci-
young children more frequently than adults. Bacterial infections of the dence in late summer and early autumn. It may also be the most
intestine cause diarrhea via direct invasion of the intestinal mucosa, common bacterial cause of diarrhea outbreaks in daycare settings. The
followed by intraepithelial cell multiplication or invasion of the lamina organism is transmitted via the fecal-oral route, most often by the
propria. Cellular invasion may be followed by the production of cyto- hands. During a 12- to 72-hour incubation period, patients may
toxin, which disrupts cell function, and/or the production of entero- develop a nonspecific prodrome characterized by fever, chills, nausea,
toxin, which alters cellular electrolyte and water balance. Bacterial and vomiting. A predominantly rectosigmoid colitis develops and
adherence to the mucosal surface may result in flattening of the micro- results in abdominal cramps and watery diarrhea. In more severe infec-
villi and disruption of normal cell functioning. Symptomatic differen- tions (bacillary dysentery), blood and mucus are passed in small, very
tiation from viral causes of diarrhea may be difficult, and sequelae of frequent stools. High fever in young infants may induce febrile sei-
infections are varied (Table 11.7). zures, and some patients may develop hemolytic uremic syndrome.
Salmonella infection. Nontyphoidal Salmonella organisms are Bacterial culture of the stool or a rectal swab, or the use of multiplex
estimated to cause 1 million annual gastrointestinal infections in the PCR assays, allows for differentiating this organism from other patho-
United States. The attack rate is highest in infancy; the incidence of gens. If positive, antibiotic treatment is usually indicated.
symptomatic infections is lower in patients older than 6 years. Salmo- Campylobacter infection. Many animal species, including poultry,
nella infection may cause an asymptomatic intestinal carrier state (rare farm animals, and household pets, serve as reservoirs for Campylo-
in children), enterocolitis with diarrhea, or bacteremia without gastro- bacter jejuni. Transmission occurs through ingestion of contaminated
intestinal manifestations but with subsequent local infections, such as food, especially undercooked food, and through person-to-person
meningitis or osteomyelitis. Salmonella infection is usually spread spread via the fecal-oral route. The disease is common in infants and
through contaminated water supplies or food (e.g., meat, chicken, eggs, adolescents, and both daycare and college outbreaks have been
raw milk, and fresh produce). Most infections in the United States are reported. Asymptomatic carriage is uncommon. Campylobacter infec-
sporadic rather than epidemic. Although an infected food handler may tion causes disease that may range from mild diarrhea to frank dysen-
contaminate food sources, farm animals or pets are often the vector. tery. The organism causes diffuse, invasive enteritis that involves the
Cats, turtles, lizards, snakes, and iguanas may also harbor Salmonella ileum and colon. Fever, cramping, abdominal pain, and bloody diar-
organisms. Outbreaks may occur among institutionalized children; rhea are characteristic and may mimic symptoms of acute appendicitis
outbreaks in daycare centers are rare. or inflammatory bowel disease. Fever and diarrhea usually resolve after
After a 12- to 72-hour incubation period, gastroenteritis develops 5-7 days; prolonged illness or relapse occasionally occurs. Campylo-
and is characterized by the sudden onset of diarrhea, abdominal bacter infection is also known to cause meningitis, abscesses, pancre-
cramps and tenderness, and fever. The diarrhea is watery, with stools atitis, and pneumonia. Guillain-Barré syndrome has been reported
containing polymorphonuclear leukocytes and, on occasion, blood. after Campylobacter infection. Identification is via stool or rectal swab
The peripheral blood white blood cell count is usually normal. bacterial culture, or via multiplex PCR assay. If positive, antibiotic
treatment is indicated.
Yersinia infection. Infection with either Yersinia enterocolitica or
Y. pseudotuberculosis may cause various clinical syndromes, including
TABLE 11.2 Differentiating Osmotic from gastroenteritis, mesenteric adenitis, pseudoappendicitis, and postinfec-
Secretory Diarrhea tious reactive arthritis. The organism is present in animals and may be
Osmotic Secretory spread to humans by consumption of undercooked meat (especially
pork), unpasteurized milk, and other contaminated foods. Person-to-
Stool volume Small (<200 mL/24 hr) Large (>200 mL/24 hr)
person spread also occurs. Young children are particularly susceptible
Response to fasting Diarrhea improves Diarrhea continues to disease, and the frequency of infections increases during the summer
Stool sodium <70 >70 months.
Stool osmotic gap* >50 <50 The organisms may be identified via multiplex PCR assay or may
Stool pH <5 >6 be cultured from rectal swab or stool specimens, but selective media
are required, and the organism may not be identified via culture
*Stool osmotic gap = 290 − 2 (stool Na+ + stool K+) for several weeks. The microbiology laboratory should be notified if
TABLE 11.3 Distinguishing Isolated Carbohydrate from Isolated Fat Malabsorption

Isolated Carbohydrate Malabsorption Isolated Fat Malabsorption
Stool character Loose and watery, non–foul-smelling Bulky large stool, foul-smelling, oil droplets visible
Perianal rash/skin erosion Present Present
Signs of fat-soluble vitamin deficiency Variable Present
Stool pH Acidic (usually <6) Alkaline
Stool reducing/non-reducing substances Present Absent
TABLE 11.4 Differential Diagnosis of TABLE 11.5 Causes of Acute

Diarrhea by Pathophysiology Gastroenteritis in Children
Osmotic Diarrhea Viruses
1. Carbohydrate malabsorption • Noroviruses and other Calciviridae
• Lactose intolerance • Rotavirus
• Osmotic laxatives (lactulose, polyethylene glycol 3350) • Astrovirus
• Antacids (magnesium hydroxide) • Enteric adenovirus
• Ingestion of excessive amounts of non-absorbable sugar or sugar • Picornaviruses
alcohols (sorbitol in chewing gum, diet candy, sucralose)
Bacteria
• Dietary ingestion of excessive fructose (high-fructose corn syrup,
• Non-typhoidal Salmonella species
ingestion of high-fructose–containing fruits in excessive amounts)
• Campylobacter jejuni
• Disaccharidase deficiency (sucrose-isomaltase deficiency, glucose-
• Shigella
galactose malabsorption, maltase-glucoamylase deficiency, congenital
• Yersinia enterocolitica
lactase deficiency)
• Enteropathogenic Escherichia coli
• Gastrocolic fistula, jejuno-ileal bypass, short-bowel syndrome
• Shiga toxin-producing Escherichia coli
2. Fat malabsorption
• Salmonella typhi and Salmonella paratyphi
• Pancreatic insufficiency
• Vibrio cholarae
• Defective handling of bile acids (e.g., primary bile acid malabsorption,
• Aeromonas species
cholestasis)
• Defective mucosal lipid handling (e.g., intestinal lymphangiectasia, Protozoa
abetalipoproteinemia, chylomicron retention disease) • Cryptosporidium
3. Protein malabsorption • Giardia lamblia
• Primary enterokinase deficiency • Entamoeba histolytica
• Hartnup disease
Helminths
Secretory Diarrhea • Strongyloides stercoralis
• Normal villous architecture
• Chloride-losing diarrhea (Cl− − HCO3− exchanger defect)
• Sodium-losing diarrhea (Na+ − H+ exchanger defect)
Yersinia infection is suspected. Antibiotics are not effective in alleviat-
• Familial diarrhea syndrome (gain-of-function mutation of guanylate
ing symptoms of Yersinia enteritis or in shortening the period of bacte-
cyclase 2C)
rial excretion. Patients with extraintestinal infection should receive
• Neurogenin-3 mutation
therapy.
• Villous atrophy
Escherichia coli infection. Although E. coli comprise the predomi-
• Microvillous inclusion disease
nant normal flora in the colon, some strains are pathogenic. Diarrhea
• Tufting enteropathy
caused by E. coli can be watery, inflammatory, or bloody, depending
• Acrodermatitis enteropathica
on the strain involved. These diarrheogenic E. coli strains are classified
• Trichohepatoenteric syndrome (phenotypic or syndromic diarrhea)
into 5 major groups on the basis of serogrouping or pathogenic mecha-
• Congenital disorders of glycosylation defects
nisms: (1) enteropathogenic E. coli (EPEC), an important cause of
Autoimmune polyglandular syndrome type 1
diarrhea in infants; (2) enterotoxigenic E. coli (ETEC), a cause of diar-
Neuroendocrine tumors
rhea in infants and a cause of traveler’s diarrhea; (3) enteroinvasive E.
Inflammatory (Combination of Secretory and Osmotic) coli, a cause of watery ETEC-like illness or, less commonly, a dysentery-
1. Infectious like illness; (4) enterohemorrhagic E. coli, a cause of hemorrhagic
2. Celiac disease colitis and hemolytic uremic syndrome (HUS); and (5) enteroaggrega-
3. Inflammatory bowel disease tive E. coli, a cause of persistent diarrhea.
4. Autoimmune enteropathy and infantile-onset inflammatory bowel disease Enteric infections with E. coli are acquired via the fecal-oral route.
• Interleukin-10 and interleukin-10 receptor defects Enterohemorrhagic strains are the only diarrhea-producing E. coli
• Hyperimmunoglobulin D from mevalonate kinase deficiency presenting strains common in the United States and have been associated with
as severe neonatal colitis foodborne epidemic outbreaks transmitted in some cases by under-
• IPEX/IPEX-like syndrome cooked meat.
5. Postinfectious enteropathies EPEC is a well-established cause of infantile diarrhea, especially in
6. Eosinophilic gastroenteritis developing countries. Asymptomatic carriage is common. At least 2
7. Idiopathic separate mechanisms are responsible for diarrhea: adherence to intes-
tinal epithelial cells leading to villous injury and mucosal inflamma-
Decreased Surface Area for Absorption tion, and production of a toxin similar to that of Shigella organisms.
1. Short-bowel syndrome Chronic infection resulting in failure to thrive may also occur.
ETEC is the major cause of traveler’s diarrhea; occasional nosoco-
IPEX, Immune dysregulation, polyendocrinopathy, enteropathy,
X-linked. mial outbreaks have also occurred in hospitalized infants. At least 3
different types of E. coli enterotoxins (heat-labile, heat-stable toxin A,
and heat-stable toxin B) have been identified. Definitive diagnosis
requires enterotoxin identification, and this method is not widely
available.
Suspecting a
foodborne illness
Vomiting is the Diarrhea is the

predominant predominant symptom
symptom (usually (1–7 days)
within 6 hr)
Watery Diarrhea with

diarrhea blood and mucus
and fever
• Staphylococcus aureus (dairy, produce, • Clostridium perfringens • Nontyphoidal salmonellosis

meats, eggs, and salads contaminated (meat, poultry, and (meat, poultry, fresh produce,
with staphylococcal enterotoxins) gravy) peanut butter, eggs)
• Bacillus cereus (cooked rice or other • ETEC and enteric • Campylobacter (poultry)
prepared foods left out at room viruses (contaminated • Enterohemorrhagic toxigenic
temperature and contaminated with food and water) Escherichia coli (e.g., 0157:H7
enterotoxin) • Cryptosporidium parvum EHEC or STEC) (ground beef,
• Noroviruses (bovine fecal contamination unpasteurized juice, raw fruits
• Anisakiasis (parasitic nematode found in of water, unpasteurized and vegetables)
raw seafood) milk, or fresh produce) • Shigella (salads, poultry, dairy
• Cyclospora cayetanesis products, raw vegetables)
(berries, fresh basil) • Vibrio parahemolyticus (raw
• Intestinal tapeworms shellfish)
(undercooked beef, • Yersinia (undercooked pork,
pork, and fish) unpasteurized milk or
fecally-contaminated water)
FIGURE 11.1 Differentiating causes of foodborne illness. EHEC, enterohemorrhagic E. coli; ETEC, entero-
toxigenic E. coli; STEC, Shiga toxin–producing E. coli.
TABLE 11.6 Assessment of Degree of Dehydration

Signs and Symptoms
General Appearance Mild Moderate Severe
Infants/young children Thirsty; alert; Thirsty; restless or Drowsy or lethargic; limp, cold, sweaty, cyanotic
restless listless
Older children Thirsty; alert; Thirsty; alert (usually) Usually conscious (but at reduced level),
restless apprehensive; cold, sweaty, cyanotic extremities;
wrinkled skin on fingers/toes; muscle cramps
Tachycardia Absent Present Present
Palpable pulses Present Present (weak) Decreased
Blood pressure Normal Orthostatic hypotension Hypotension
Cutaneous perfusion Normal Normal Reduced/mottled
Skin turgor Normal Slight reduction Reduced
Fontanel Normal Slightly depressed Sunken
Mucous membranes Moist Dry Very dry
Tears Present Present/absent Absent
Respirations Normal Deep, may be rapid Deep and rapid
Urine output Normal Oliguria Anuria/severe oliguria
From Lewy JE. Nephrology: Fluids and electrolytes. (Modified from World Health Organization Guide.) In: Behrman RE, Kliegman RM, eds.
Nelson Essentials of Pediatrics. 2nd ed. Philadelphia: WB Saunders; 1994:582.
TABLE 11.7 Complications of Bacterial Enteric Infections

Complication Important Bacterial Agents Clinical Considerations
Dehydration Vibrio cholerae, any bacterial enteropathogen Complication of all forms of acute watery diarrhea; should prompt
aggressive fluid and electrolyte replacement
Bacteremia Salmonella, Campylobacter fetus Organisms that deeply penetrate the intestinal mucosa are prone to cause
bacteremia; certain high-risk conditions predispose to systemic
Salmonella infection
Hemolytic uremic Shiga toxin–producing Escherichia coli, Shiga toxin is absorbed, causing injury to endothelial cells of the
syndrome Campylobacter jejuni glomerular capillaries with intravascular coagulation
Guillain-Barré Campylobacter, Salmonella, Shigella flexneri, Most cases occur as a result of molecular mimicry, with antibodies
syndrome Yersinia directed to Campylobacter lipooligosaccharides and peripheral nerve
gangliosides; probability of development of Guillain-Barré syndrome
within 2 mo after Campylobacter infection estimated at <2/10,000 cases
Reactive arthritis and Inflammatory bacterial pathogens (e.g., Occurs in 2.1/100,000 cases of Campylobacter infection and 1.4/100,000
iritis Campylobacter) are most important, but most cases of Salmonella infection; affected persons may be HLA-B27–
bacterial pathogens can produce the positive or HLA-B27–negative
syndrome
Postinfectious irritable Vibrio cholerae, any bacterial enteropathogen Enteric bacterial infection with intestinal inflammation in a susceptible
bowel syndrome host leads to altered intestinal findings and postinfectious irritable
bowel syndrome; duration is ≥5 yr
Enterohemorrhagic E. coli produces a Shiga-like cytotoxin and disease, gastrointestinal surgery or procedures, and immunocompro-
causes diarrhea, hemorrhagic colitis, and, in about 20% of infected mised status.
persons, hemolytic uremic syndrome (HUS). Both epidemic and spo- C. difficile infection should be considered in patients in whom diar-
radic cases have been recognized. Infection is more common in the rhea develops during or within several weeks of antibiotic therapy.
summer and fall. A particular serotype, E. coli 0157 : H7, has been Illness associated with this organism varies from a mild, self-limited,
linked to the development of HUS in young children. The most nonbloody diarrhea to severe hemorrhagic colitis, protein-losing
common manifestations of enterohemorrhagic E. coli infection begin enteropathy, toxic megacolon, colonic or cecal perforation, peritonitis,
with severe abdominal cramps and watery diarrhea, followed by grossly sepsis, shock, and death. In rare cases, manifestations of C. difficile
bloody stools and emesis. Fever is uncommon. Fecal leukocytes are infection include fever or abdominal pain without diarrhea.
absent or few. Other manifestations include asymptomatic infection The colitis is caused by potent toxins produced by the organism:
and watery diarrhea without progression to hemorrhagic colitis. E. coli toxin A, a lethal enterotoxin that causes hemorrhage and fluid secre-
0157 : H7 is cleared from the stool in 5-12 days. If HUS develops, tion in the intestines; and toxin B, a cytotoxin detectable by its cyto-
symptoms become noticeable in the week after the onset of diarrhea pathic effects in tissue culture. Both toxins play a role in disease
and consist of renal failure, microangiopathic hemolytic anemia, production, although toxin A may be more important.
thrombocytopenia, and diarrhea. There is no role for antimicrobial C. difficile infection is currently diagnosed either by enzyme immu-
therapy in enterohemorrhagic E. coli disease. Antibiotics neither noassay for toxins in stool or by nucleic acid amplification tests that
shorten the duration of disease nor prevent progression to HUS; they identify the microbial toxin genes in unformed stool. Sigmoidoscopy
may predispose to HUS. or colonoscopy reveals pseudomembranes in 30-50% of cases, typically
Clostridium difficile infection. Clostridium difficile causes acute in association with more severe disease. Treatment is indicated for
and chronic diarrhea in children when the normal colonic flora is severe disease.
disrupted. Pseudomembranous colitis is the most severe form of this Aeromonas infection. Aeromonas species are gram-negative bacilli
infection, occurring as a result of a severe inflammatory response to that are found in a variety of freshwater sources and that are capable
the C. difficile toxins. Transmission occurs through person-to-person of causing a wide array of disease, including a mild, self-limited
contact and through environmental contamination via the spores diarrheal illness in children. Occasionally, Aeromonas may cause dys-
formed by C. difficile, which retain viability for up to 1 week on dry entery or a protracted diarrheal illness. The most common manifes-
surfaces. tation is a watery, nonbloody, nonmucoid diarrhea seen during the
The prevalence of carrier status for C. difficile in healthy, asymp- late spring, summer, and early fall. More severe infections may
tomatic outpatients is as high as 50% in healthy infants, but is usually resemble ulcerative colitis, with chronic bloody diarrhea and abdomi-
less than 5% in patients over 5 years of age. C. difficile and its toxin nal pain.
have been identified in the feces of healthy infants in concentrations Plesiomonas infection. Plesiomonas shigelloides is a Vibrio-like
similar to those found in adults with pseudomembranous colitis. The organism found in soil and water that is sometimes implicated in
apparent resistance of infants to C. difficile and its toxin is related to childhood diarrhea. It has been linked to consumption of raw shellfish
the developmental absence of the toxin-binding site in the immature or contaminated water, exposure to reptiles and tropical fish, and travel
intestine. Asymptomatic carriage rates in hospitalized patients may be to Mexico and Asia. After an incubation period of 1-2 days, patients
as high as 20%. Infection is highly associated with recent antibiotic typically develop watery diarrhea and vomiting, although some may
exposure, particularly to broad-spectrum antibiotics, which disrupt develop dysentery. Diagnosis is via stool culture. Symptoms may last
the endogenous colonic flora that inhibits the growth of C. difficile. up to 2 weeks, although the disease is typically self-limited in immu-
Other risk factors for C. difficile diarrhea include inflammatory bowel nocompetent individuals.
Parasitic Diarrhea TABLE 11.8 Medications and Substances

Giardiasis. Giardia intestinalis is a flagellated protozoan that can
Associated with Diarrhea in Children
cause diarrhea, malabsorption, abdominal pain, and weight loss. It Agent Mechanism
spreads through contaminated food and water, as well as through Stimulant laxatives (e.g., senna, Increased intestinal secretion
person-to-person contact via the fecal-oral route. The latter mode of bisacodyl) (phenolphthalein, bisacodyl)
transmission is responsible for outbreaks of diarrhea in daycare centers
Antacids Osmotic effect (Mg2+)
and residential facilities. Infection is often asymptomatic. Symptom-
atic illness usually develops 1-3 weeks after exposure and may mimic Prokinetic agents Increased peristalsis (metoclopramide,
acute gastroenteritis with low grade or no fever, nausea, vomiting, and bethanechol, cisapride)
watery diarrhea. In some patients, a chronic illness develops, character- Measles-mumps-rubella vaccine Unknown
ized by intermittent, foul-smelling diarrhea, abdominal bloating, Thyroid hormone Increased peristalsis
nausea, abdominal pain, and weight loss. Up to 40% of patients may Chemotherapeutics Intestinal mucosal injury
develop secondary lactase deficiency following infection. Diagnosis is Heavy metals Toxic effect
via EIA or direct fluorescent antibody (DFA) tests, which offer superior
Organophosphates Cholinergic effects
sensitivity and specificity compared to microscopy. If microscopy is
performed, three separate samples of fresh stool should be examined Diuretics Unknown
for cysts or trophozoites, because excretion of the organism is only Digitalis Unknown
intermittent. Treatment is typically indicated in the presence of symp- Colchicine Unknown
toms, to prevent institutional outbreaks, or to prevent spread to immu- Indomethacin Prostaglandin synthesis inhibition
nocompromised individuals.
Theophylline Increased peristalsis
Entamoeba histolytica infection. Entamoeba histolytica is acquired
in warm climates via the ingestion of cysts in fecally contaminated food
or water. Infected individuals are often asymptomatic. Amebic dysen-
tery may occur, but hepatic abscess and other remote infections are diagnosis is based on the typical historical presentation. Treatment is
uncommon. Because cysts are shed in the stool on an intermittent supportive; antibiotics are not indicated.
basis, examination of several fecal specimens may be required for iden- Bacillus cereus, a gram-positive sporulating organism found in
tification. Stool antigen detection assays allow for differentiation soil, is usually associated with contamination of refried rice or vegeta-
between E. histolytica and the more prevalent though less pathogenic bles. Two food poisoning syndromes can occur. A short incubation
E. dispar, which may also be detected on microscopy. Treatment is period disease (1-6 hours) results from ingestion of preformed toxin
indicated to prevent the development of extraintestinal manifestations and is characterized by nausea, vomiting, and diarrhea, similar to
or spread to other individuals. staphylococcal food poisoning. A long incubation period disease (8-16
Cryptosporidium infection. This intracellular protozoan causes hours) is caused by in vivo production of an enterotoxin and is char-
watery diarrhea in both immunocompetent and immunocompro- acterized by abdominal pain, tenesmus, and profuse watery diarrhea.
mised hosts and is an important cause of severe diarrhea in individuals Vomiting is usually absent. Both syndromes resolve spontaneously
infected with the human immunodeficiency virus. Cryptosporidium within 24 hours and are managed with supportive care.
has also been recognized as an occasional cause of self-limited diarrhea Clostridium perfringens food poisoning has been associated with
in travelers, as well as in children in daycare centers and persons in ingestion of contaminated beef and poultry. The disease results from
residential institutions. The mechanisms by which these organisms the production and release of an enterotoxin into the lower bowel 8-24
cause diarrhea are unknown. Nucleic acid amplification assays and EIA hours after ingestion of the vegetative form of the organism. Onset is
tests are available for diagnosis. Identification via microscopy requires sudden, with abdominal pain and watery diarrhea. Fever and vomiting
specialized staining techniques that should be requested if Cryptospo- are absent. Treatment is supportive.
ridium infestation is suspected.
Other Causes of Acute Diarrhea CHRONIC DIARRHEA

Parenteral secondary diarrhea. Acute diarrhea that accompanies The etiology of chronic diarrhea is dependent on the age of the patient
infections outside of the gastrointestinal tract is termed parenteral (see Table 11.1) and is additionally influenced by socioeconomic
diarrhea. Upper respiratory tract and urinary tract infections may be factors and the clinical setting. In developing countries, chronic diar-
associated with increased bowel movement frequency or stool water. rhea is frequently caused by acute infections, as malnutrition tends to
The mechanism is unclear but may involve alterations in bowel motil- prolong the course of infectious enterocolitis. The most common eti-
ity, changes in diet, or the effects of antibiotic treatment. ologies of chronic diarrhea in developed countries are functional intes-
Medications. Various nonlaxative prescription and over-the- tinal disorders, nutrient malabsorption (cystic fibrosis), celiac disease,
counter medications may cause acute diarrhea (Table 11.8). The most and inflammatory bowel diseases, but persistent infections of the intes-
commonly implicated agents are antibiotics, acting through mecha- tinal tract may also occur.
nisms other than C. difficile.
Food poisoning (Table 11.9; see Fig. 11.1). Staphylococcal food History
poisoning results from ingestion of preformed enterotoxin, produced The history should establish the age of onset, as well as the frequency
in contaminated food that has incubated at or above room tempera- and nature of the stools, including the presence of blood, nighttime
ture for a suitable period. Staphylococcal food poisoning is suggested stooling, urgency, weight loss, and any associated systemic symptoms.
by the sudden onset of vomiting that is followed by explosive diarrhea, History should also ascertain any recent travel, other sick contacts, or
usually within 4-6 hours after ingestion of the contaminated food. The swimming in freshwater sources. A history of recurrent infections, use
illness is self-limited and usually resolves within 12-24 hours. The of intravenous drugs, or other signs, symptoms, or risk factors for
TABLE 11.9 Foodborne Gastrointestinal Illnesses

Incubation
Cause Period Clinical Clues Common Vehicle Diagnosis
Monosodium Minutes to 2 hr Burning in abdomen, chest, Found in some Asian cuisines Large amount of monosodium
glutamate extremities, and neck; glutamate in implicated food
lightheadedness; chest pain
Heavy metals (copper, Minutes to 2 hr Metallic taste, diarrhea, Carbonated or acidic beverages in Chemical study of implicated
zinc, cadmium, tin) prominent vomiting, no fever metal containers beverage
Mushroom poisoning* Minutes to 2 hr Altered mental status with visual Noncommercially obtained Identify mushroom and/or toxic
disturbance (encephalopathy) mushrooms chemical (e.g., muscarine,
psilocybin)
Fish/Shellfish-Related Toxins*
Scombrotoxin Minutes to 2 hr Histamine reaction: flushing, Scombridae fish (includes tuna, Identify fish and/or chemical toxin
poisoning headache, dizziness, burning of mackerel, and bonito species), (ciguatoxin, tetrodotoxin, histamine,
throat and mouth mahi-mahi etc.)
Paralytic shellfish Minutes to 2 hr Paresthesia, dizziness, Mussels, clams, oysters, scallops
poisoning sometimes paralysis contaminated with toxins, typically
from dinoflagellate algae species
Tetrodotoxin Minutes to 2 hr Paresthesia Various pufferfish and angelfish
poisoning species. The toxin is produced by
symbiotic or infecting bacteria in
the fish species
Ciguatoxin 2-24 hr Itching, arthralgias, metallic Barracuda, red snapper, grouper,
poisoning taste, Paresthesias, cramps, amberjack
visual disturbances, “Loose”
painful teeth
Norovirus 24-48 hr Epidemic watery diarrhea Contaminated ice machines, shellfish, Nucleic acid amplification assays
ready-to-eat foods
Staphylococcal 2-8 hr Prominent vomiting, no fever, Ham, poultry, pastries (cream-filled), Identification of preformed toxin or
enterotoxins duration less than 24 hr mixed salads, egg salad isolation of 105 colony-forming-
units of organism from food
Bacillus cereus
Emetic form: short 2-8 hr Prominent vomiting, no fever, Fried rice, macaroni-and-cheese, Identification of preformed toxin or
incubation duration less than 48 hr vegetables, other ready-to-eat foods isolation of 105 colony-forming-
left at room temperature. Symptoms units of organism from food
and rapidity of onset are due to
presence of preformed toxin
Diarrheal form: 8-14 hr Abdominal cramps, severe Fried rice, macaroni-and-cheese, Identification of preformed toxin or
longer incubation diarrhea, no fever, duration vegetables, other ready-to-eat foods isolation of 105 colony-forming-
less than 48 hr left at room temperature. Symptoms units of organism from food or
are due to in vivo toxin production stool
Clostridium perfringens 8-14 hr Abdominal cramps, severe Meat, poultry, gravy Identification of preformed toxin or
diarrhea, no fever, duration isolation of 105 colony-forming-
less than 48 hr units of organism from food or
stool
Enterotoxigenic 12 hr to several Abdominal cramps, watery Incomplete data (rarely reported) Identification of enterotoxin or
Escherichia coli days diarrhea may be prolonged up isolation of organism from stool
(ETEC) to 7 days
Invasive Escherichia 12 hr to days Prolonged febrile diarrhea and/or Incomplete data (rarely reported) Isolation of organism from stool
coli dysentery
Vibrio cholerae 12 hr to days Abdominal cramps, watery Contaminated food and water (very Isolation of organism from food or
diarrhea (rice-water stools). rare in United states) stool
May be prolonged up to 1 wk
Vibrio parahemolyticus 12 hr to days Prolonged febrile diarrhea and/or Seafood Stool culture (or food culture)
dysentery
Continued
TABLE 11.9 Foodborne Gastrointestinal Illnesses—cont’d

Incubation
Cause Period Clinical Clues Common Vehicle Diagnosis
Shigella species 12 hr to days Prolonged febrile diarrhea and/or Fish, mixed salads Stool culture (or food culture)
dysentery
Campylobacter species 12 hr to days Prolonged febrile diarrhea and/or Unpasteurized milk, poultry or meat Stool culture (or food culture)
dysentery
Clostridium botulinum 12 hr to days Diarrhea, constipation Home-canned foods, fish, honey Botulinum toxin in food, stool, and
Guillain-Barré syndrome serum
Yersinia enterocolitica Uncertain Prolonged diarrhea and/or Milk, pig intestine Stool culture
dysentery
*Potentially dangerous; observation in hospital often required.

Modified from Reilly BM. Practical Strategies in Outpatient Medicine. 2nd ed. Philadelphia: WB Saunders; 1991:888.
immunodeficiency should be documented. Family history should

TABLE 11.10 Red Flags in the Evaluation
be probed for the presence of gastrointestinal disorders or
immunodeficiency.
of Diarrhea
Presence of blood in stools
Physical Examination Persistent right upper or right lower quadrant abdominal pain
Hydration status should be assessed. Growth parameters should be
Involuntary weight loss or growth failure
obtained and charted on appropriate age-matched growth charts. The
physical examination should assess for signs of malnutrition, vitamin Delayed puberty
and micronutrient deficiency, and dermatologic manifestations of sys- Presence of associated symptoms, such as unexplained fever, suggesting
temic diseases. Jaundice may suggest hemolysis or hepatic dysfunction. inflammatory arthritides or other systemic diseases
Signs of fat-soluble vitamin deficiency include bone deformities in Nocturnal fecal urgency or diarrhea
vitamin D deficiency, dry scaly skin and Bitot spots in vitamin A defi- Perirectal/perianal disease
ciency, hyporeflexia or gait abnormalities in vitamin E deficiency, and Persistent dysphagia
bruises or bleeding in vitamin K deficiency. Joint examination may
reveal arthritis associated with inflammatory bowel disease. Abdomi-
nal examination may reveal evidence suggestive of neuroendocrine elastase suggests pancreatic insufficiency. Elevated levels of stool
tumors, and perianal examination may reveal evidence of inflamma- alpha-1-antitrypsin (A1AT) are suggestive of protein-losing enteropa-
tory bowel disease (fistula, skin tags). thy (PLE). Elevated fecal calprotectin or fecal lactoferrin are indica-
tive of intestinal inflammation. The presence of fecal leukocytes or
Diagnostic Evaluation occult blood may indicate mucosal inflammation as well, though
The clinician should attempt to focus the diagnostic evaluation on only neither is sufficiently sensitive nor specific.
those conditions suggested by the history and physical examination. Blood tests should include a complete blood count to evaluate for
Invasive diagnostic procedures should be limited to those patients anemia and thrombocytosis, which may suggest blood loss and inflam-
whose presentation contains red flags for serious disease (Table 11.10). mation, respectively. In the presence of anemia, red blood cell indices
Laboratory investigation should begin with microbiologic studies for may reveal a microcytosis potentially indicative of iron deficiency or a
bacteria and parasites in the stool. Acute infection with bacteria, such macrocytosis suggestive of vitamin B12 or folate deficiency. A normo-
as Yersinia, E. coli, and Salmonella may develop into a chronic illness cytic anemia may be seen in chronic inflammatory diseases. White
and can be detected by routine stool cultures and multiplex PCR blood cell count and differential and quantification of immunoglobu-
assays. C. difficile testing should be performed, especially in the pres- lins A, G, and M screen for immune disorders. Erythrocyte sedimenta-
ence of risk factors. Antigen detection and PCR-based assays for tion rate (ESR) and C-reactive protein (CRP) support inflammation
Giardia and Cryptosporidium are more sensitive and specific than but are nonspecific. Low albumin could be indicative of a chronic
routine microscopy-based examinations and are indicated if these inflammatory process or PLE. Elevated anti-tissue transglutaminase
infections are suspected. immunoglobulin A (IgA) antibody is sensitive and specific for celiac
Except in the setting of neonatal-onset diarrhea, stool electrolytes disease, but a low total serum IgA level may result in a false-negative
and osmolality are of limited use. The differentiation of osmotic and test. Levels of the fat-soluble vitamins A, 25-OH vitamin D, vitamin E,
secretory diarrhea is typically made by a trial of fasting and determin- and vitamin K (reflected by prothrombin time) may be measured if fat
ing if there is improvement in the stool output: osmotic diarrhea malabsorption is suspected.
improves or resolves upon fasting, whereas secretory diarrhea does not. The algorithmic approach to evaluating chronic diarrhea is depicted
Stool-reducing substances are positive in the setting of osmotic diar- in Fig. 11.2A and B and is enumerated in Table 11.11.
rhea secondary to carbohydrate malabsorption. In patients with
osmotic diarrhea and negative reducing substances, it is essential to Disorders of Carbohydrate Malabsorption
determine whether steatorrhea is present. If qualitative assays for fecal The brush border epithelium of the small bowel contains enzymes
fat are negative, a more precise indication of steatorrhea may be necessary for carbohydrate digestion. These enzymes hydrolyze disac-
obtained by quantifying fecal fat and calculating the coefficient of fat charides and oligosaccharides into monosaccharides that are then
absorption, which requires a 72-hour collection of stool. Low fecal absorbed by transporters on the luminal surface of enterocytes.
Carbohydrate malabsorption is secondary to either deficiency of a and starch. Exposure to these products leads to osmotic diarrhea,
particular enzyme (e.g., congenital sucrase-isomaltase deficiency) or pain, bloating, abdominal distention, and at times, chronic mal-
an abnormality in a transport protein involved with the absorption of nutrition and failure to thrive. The sucrase-isomaltase gene is located
monosaccharides (e.g., glucose-galactose malabsorption). The onset of on chromosome 3 (3q25.2-q26.2) and more than 25 mutations in
various carbohydrate malabsorption syndromes can vary based on the the gene have been identified. These mutations result in a variety
timing of the introduction of particular carbohydrates (Table 11.12). of defects in the structure and function of the enzyme, including
Patients with carbohydrate malabsorption disorders present with isolated deficiencies in sucrase activity or isomaltase activity. This
severe watery diarrhea, which results from osmotic action exerted by genetic heterogeneity results in phenotypic variability ranging from
the malabsorbed carbohydrate in the intestinal lumen. Colonic bacte- completely absent to low-residual sucrase activity, and from com-
ria ferment the malabsorbed sugars, which generates a mixture of gases pletely absent to normal isomaltase activity. Because sucrase-
(e.g., hydrogen, methane, and carbon dioxide) and short-chain fatty isomaltase is responsible for up to 80% of the maltase activity in
acids. These gases form the basis of carbohydrate-specific breath the brush border, maltase activity is significantly reduced in almost
hydrogen testing, which is often used in diagnosis. The stools become all cases.
acidified to a pH of less than 7, which can lead to diaper dermatitis. The exact prevalence of CSID is unclear, although rates are as high
as 10% in the Greenland Inuit population, 7% in Canadians of native
Disaccharidase Deficiency ancestry, and about 3% in Alaskans of native ancestry. Estimates of the
Congenital sucrase-isomaltase deficiency (CSID). CSID is an prevalence of CSID in other North American and European popula-
inherited deficiency of the ability to hydrolyze sucrose, maltose, tions generally range from 1 in 500 to 1 in 2000 among non-Hispanic
CHRONIC DIARRHEA IN INFANTS <6 MONTHS OF AGE
Blood-tinged diarrhea
YES NO
Stool culture Weight loss or poor weight gain

± Clostridium difficile toxin
NO YES
Abnormal Normal Stool studies for: Consider:

results results Ova and parasites Stool for blood, fecal leukocytes,
pH ova and parasites, fecal fat
Food protein–induced Reducing substances Stool culture
enterocolitis syndrome Stool culture and/or Stool for Giardia antigen
(see Chapter 13) nucleic acid Clostridium difficile toxin
amplification assays CBC
ALT
GGT
Bacterial Sweat chloride
gastroenteritis Stool and serum electrolytes
Clostridium Abnormal Normal Serum zinc level
difficile results results Immunoglobulins
Postinfectious enteritis Postinfectious

Protozoa (Giardia, enteritis
Cryptosporidium) Excessive juice
Excessive juice (sorbitol) intake Abnormal Normal
(sorbitol) intake Hirschsprung results results
Carbohydrate malabsorption disease
(congenital disaccharidase
deficiciency)
Cystic fibrosis Food protein–induced
Bacterial gastroenteritis
Protozoa (e.g., Giardia) enteropathy
Shwachman-Diamond Postinfectious
syndrome enteritis
Hepatic disorders Excessive juice
(cholestastasis) (sorbitol) intake
Immune deficiency Protein-calorie
Autoimmune enteropathy malnutrition
(IPEX/IPEX-like disorders) Factitious disorder by
Congenital chloride-losing proxy
diarrhea Microvillus inclusion
Bacterial gastroenteritis disease
Acrodematitis enteropathica
A
FIGURE 11.2 A, The algorithmic approach to chronic diarrhea in infants <6 months of age. ALT, alanine
aminotransferase; CBC, complete blood count; GGT, gamma-glutamyl transferase; IPEX, immune dysregula-
tion, polyendocrinopathy, enteropathy, X-linked. Continued
CHRONIC DIARRHEA IN INFANTS >6 MONTHS OF AGE ( >2 WEEKS’ DURATION)
Consider:
Stool for blood, pH, reducing substances, ova and parasites
Giardia antigen
Cryptosporidium antigen
Stool culture
Clostridium difficile toxin
Abnormal
results
YES NO
Weight loss or
poor weight gain
YES NO
Bacterial gastroenteritis Consider: Excessive juice (sorbitol) intake

Protozoa (Giardia) Stool studies for fecal leukocytes, fat, alpha-1-antitrypsin, Chronic nonspecific diarrhea (toddler’s
Clostridium difficile and elastase diarrhea)
Postinfectious enteritis CBC with differential Postinfectious enteritis
Disaccharidase deficiencies ALT Lactose intolerance
Inflammatory bowel disease GGT Irritable bowel syndrome
ESR Constipation with overflow incontinence
CRP Laxative abuse
HIV testing Factitious disorder or factitious disorder by proxy
Sweat chloride
Anti-tissue transglutaminase immunoglobulin A
Serum immunoglobulins
Serum zinc level (if rash present)
Postinfectious enteritis
Congenital disaccharidase deficiencies
HIV
Cystic fibrosis
Shwachman-Diamond syndrome
Celiac disease
Immune deficiency
Autoimmune enteropathy (IPEX/IPEX-like disorders)
Food protein–induced enteropathy
Hepatic disorders (cholestastasis)
Inflammatory bowel disease
Acrodematitis enteropathica
Protein-calorie malnutrition
Intestinal telangectasias
B
FIGURE 11.2, cont’d B, The algorithmic approach to chronic diarrhea in children >6 months of age. ALT,
alanine aminotransferase; CBC, complete blood count; CRP, C-reactive protein; ESR, erythrocyte sedimenta-
tion rate; GGT, gamma-glutamyl transferase; HIV, human immunodeficiency virus; IPEX, immune dysregula-
tion, polyendocrinopathy, enteropathy, X-linked. (Modified from Pomeranz AJ, Sabnis S, Busey SL, Kliegman
RM, eds. Pediatric Decision-Making Strategies. 2 ed. Philadelphia: Elsevier; 2016:87-89.)
whites, with a lower prevalence in African Americans and whites of develop an increased capacity to ferment residual sucrose and the
Hispanic descent. intestinal tract develops an increased capacity for reabsorption. Patients
The classic presentation of CSID is severe watery diarrhea, failure may be misdiagnosed as having food allergies or irritable bowel syn-
to thrive, irritability, and diaper dermatitis in a 9- to 18-month-old drome, or may remain undiagnosed. Symptoms may abate with the
infant who has been exposed to sucrose and starch in the form of fruit restriction of carbohydrate in the diet or with the use of enteral sucrase
juices, fruit purees, and starch-laden foods such as crackers and cookies enzyme supplements.
(see Table 11.4). Intrinsic factors that contribute to the severity of Diagnosis typically requires endoscopy for histologic examination
presentation during infancy include the shorter length of the colon and of small bowel morphology and measurement of disaccharidase levels
a decreased capacity for colonic reabsorption of fluid and electrolytes, on biopsy specimens. Diagnosis requires the following:
more rapid small intestinal transit, a high carbohydrate diet, and lower 1. Normal small bowel morphology
levels of amylase prior to 2 years of age. Some patients with milder 2. Absent or markedly reduced sucrase activity
sucrase deficiency may improve with age as their colonic bacteria 3. Isomaltase activity varying from absent to full activity
4. Reduced maltase activity

TABLE 11.11 Diagnostic Studies in the
5. Normal lactase activity, or in the setting of reduced lactase, a
Evaluation of Chronic Diarrhea sucrase : lactase ratio of <1.0.
Initial Studies Other less invasive methods of diagnosis include sucrose breath
Stool examination for blood, leukocytes, reducing substances, and hydrogen quantification and differential urinary disaccharide assess-
Clostridium difficile toxin; stool examination for ova and parasites and ment; however, both of these modalities are associated with high false-
cultures for infectious bacterial pathogens positive and false-negative rates. Furthermore, differential urinary
Complete blood count disaccharide testing requires a 10-hour urine collection specimen,
which is often impractical in infants and younger children.
Serum electrolytes, blood urea nitrogen, creatinine, calcium, phosphorus,
Maltase-glucoamylase deficiency. Maltase-glucoamylase is a
albumin, total protein
brush border hydrolase that serves as an alternate pathway for starch
Urinalysis and culture digestion that complements sucrase-isomaltase activity. Congenital
Stool electrolytes maltase-glucoamylase deficiency is rare, with only several cases
described in the literature. Genetically, maltase-glucoamylase shares
Second-Phase Studies approximately 59% of its sequence with sucrase-isomaltase, and the
Sweat chloride test enzyme has two catalytic sites that are identical to those of sucrase-
Breath analysis isomaltase. Symptoms are similar to those seen in CSID. Diagnosis
d-Xylose test requires the demonstration of reduced glucoamylase activity in the
Serum carotene, folate, vitamin B12, and iron levels setting of normal small bowel histology and normal pancreatic amylase
activity.
Fecal alpha-1-antitrypsin level
Congenital glucose-galactose malabsorption (CGGM). Congenital
Fecal fat studies or coefficient of fat absorption studies glucose-galactose malabsorption results from defective sodium-
Fatty test meal, Lundh test meal coupled transport of glucose and galactose into enterocytes. It is a
rare autosomal recessive disorder that results from mutations in the
Third-Phase Studies sodium-glucose cotransporter gene SGLT1 located on chromosome
Fat-soluble vitamin levels: A, 25-hydroxy D, and E 22q12.3. CGGM presents as a neonatal-onset profuse, watery diarrhea
Contrast radiographic studies: upper gastrointestinal series or barium that ceases immediately following the elimination of glucose and galac-
enema tose sources from the diet. Symptoms recur if the patient is fed formula
Small intestinal biopsy for histology and mucosal enzyme determination containing either of these carbohydrates, including polymers such as
Bentiromide excretion test sucrose and lactose. The disorder may lead to dehydration and elec-
trolyte abnormalities, both of which can become life-threatening, and
Specialized Studies patients may be hypoglycemic. Stool-reducing substances are positive
Schilling test secondary to the presence of glucose in the stools. Intestinal morphol-
Serum/urine bile acid determination ogy is normal. The diagnosis can be further established by an abnormal
Endoscopic retrograde pancreatography glucose breath hydrogen test and SGLT1 sequencing, although neither
is required to confirm the diagnosis.
Provocative pancreatic secretion testing
Congenital lactase deficiency. A rare autosomal recessive disorder
From Wyllie R, Hyams JS, eds. Pediatric Gastrointestinal Disease. leading to very low or complete absence of brush border lactase-phlo-
2nd ed. Philadelphia: WB Saunders; 1999:283. rizin hydrolase activity, congenital lactase deficiency usually presents
with diarrhea starting soon after the introduction of breast milk or any
lactose-containing formula. Most infants manifest within the first 10
days of life. Unless the disorder is recognized and treated quickly, the
condition is life-threatening secondary to dehydration and electrolyte
abnormalities. Small bowel biopsies reveal normal histology although
TABLE 11.12 Typical Age of Presentation low or completely absent lactase concentrations. A presumptive diag-
of Carbohydrate Malabsorption Syndromes nosis can be made if osmotic diarrhea in a neonate resolves by intro-
ducing lactose-free formula.
Carbohydrate Malabsorption Primary lactase deficiency (lactose intolerance). Approximately
Syndrome Age of Symptom Onset 65% of the world’s population has primary lactase deficiency, although
Congenital glucose-galactose Neonatal period prevalence varies by ethnicity. While primary lactase deficiency is
malabsorption nearly universal in Asian and Native American populations and is as
Congenital lactase deficiency high as 80% in Hispanic, African American, and Ashkenazi Jewish
Sucrase-isomaltase deficiency Weaning age populations, as few as 2% of individuals of northern European ances-
Glucoamylase deficiency try are affected. Age of onset varies by ethnicity as well. Approximately
Primary lactase deficiency Uncommon before 2 or 3 yr of age 20% of Hispanic, Asian, and African American children younger than
Around 5 yr of age in Asians, 5 years of age are affected, whereas white children typically do not
Hispanics, and African American develop symptoms of lactose intolerance until after 5 years of age.
populations Children with clinical signs of lactose intolerance at an earlier age than
Over 5 yr of age, more typically in would be typical for their ethnicity may warrant an evaluation for an
adolescence in Caucasians of alternate cause.
European decent Symptoms typically develop insidiously over the course of many
years, with most affected individuals experiencing onset of symptoms
in late adolescence or adulthood. Within 30 minutes to 2 hours of Diagnostic evaluation should be directed toward these entities when
ingesting lactose, patients develop abdominal cramping and disten- secondary lactase deficiency is suspected and an infectious etiology is
tion, foul-smelling flatulence, nausea, and diarrhea. While the severity not found.
of symptoms is directly correlated with the quantity of ingested lactose, Severe malnutrition can also produce secondary lactose intolerance
each individual exhibits a unique dose threshold beyond which he or via small bowel atrophy. Most infants and children with malabsorption
she becomes symptomatic. attributable to malnutrition are able to continue to tolerate dietary
Diagnosis is suggested historically. When lactose intolerance is sus- carbohydrates, including lactose. However, the World Health Organi-
pected, a trial of a lactose-free diet can assist in confirming the diagno- zation recommends avoidance of lactose in children with persistent
sis. Patients must be sure to eliminate all sources of lactose, including postinfectious diarrhea lasting more than 14 days, if they fail a dietary
some that may be hidden (Table 11.13). Generally, a 2-week trial of a trial of milk or yogurt. Treatment of secondary lactase deficiency and
strict lactose-free diet producing resolution of symptoms, followed by lactose malabsorption attributable to an underlying condition gener-
a subsequent reintroduction of dairy foods resulting in recurrence of ally does not require elimination of lactose from the diet but, rather,
symptoms is diagnostic. In subtler cases, hydrogen breath testing is the treatment of the underlying condition.
least invasive and most helpful test to diagnose lactose malabsorption. Table 11.14 lists additional important causes of chronic neonatal
Secondary lactase deficiency. Secondary lactase deficiency devel- or infantile diarrhea.
ops when an inflammatory process, such as a viral infection, damages
the brush border epithelium and leads to the loss of the lactase-
containing epithelial cells from the tips of the villi. The immature
CHRONIC NONSPECIFIC DIARRHEA
epithelial cells that replace these are often lactase deficient, leading to Chronic nonspecific diarrhea, also known as functional or toddler’s
lactose malabsorption. Secondary lactase deficiency in most children diarrhea, typically affects children between 1 and 3 years of age and is
with acute gastroenteritis is rarely clinically significant. Most affected characterized by the passage of several watery and unformed stools
children can safely continue breast milk or standard lactose-containing each day. Stools are typically relatively well formed in the morning but
formula without any significant effects, although infants under 3 months become looser as the day progresses. The stools often appear to contain
of age may develop clinically significant symptoms. Giardiasis, crypto- undigested vegetable matter but lack blood, mucus, or excessive fat.
sporidiosis, and other parasites that infect the proximal small intestine Children with functional diarrhea, if offered an unrestricted and age-
often lead to lactose malabsorption from direct injury to the epithelial appropriate diet, gain weight normally. However, in an attempt to treat
cells by the parasite. Secondary lactase deficiency with clinical signs of the diarrhea, many children are placed on restrictive diets that may
lactose intolerance can be seen in celiac disease, Crohn disease, and lack dairy, fats, and occasionally starches; such restrictions lead to
immune-related and other enteropathies and should be considered if failure to thrive. Rome-III diagnostic criteria specify that all of the
children with these diagnoses have symptoms of lactose intolerance. following must be present:
1. Daily painless, recurrent passage of 3 or more large, unformed
stools
TABLE 11.13 Hidden Sources of Lactose 2. Symptoms that last more than 4 weeks
3. Onset of symptoms that begins between 6 and 36 months of age
• Bread and other baked goods
4. Passage of stools that occurs during waking hours
• Waffles, pancakes, biscuits, cookies, and the mixes to make them
5. There is no failure-to-thrive if caloric intake is adequate
• Processed breakfast foods such as doughnuts, frozen waffles and
Chronic nonspecific diarrhea is thought to be a variant of irritable
pancakes, toaster pastries, and sweet rolls
bowel syndrome (IBS), and a family history of IBS is common. The
• Processed breakfast cereals
pathophysiology may involve abnormal intestinal motility with
• Instant potatoes, soups, and breakfast drinks
decreased mouth-to-anus transit time. Excessive fruit juice intake may
• Potato chips, corn chips, and other processed snacks
also contribute to the diarrhea by overwhelming the carbohydrate
• Processed meats such as bacon, sausage, hot dogs, and lunch meats
absorptive capacity of the gut. Chronic nonspecific diarrhea is a benign
• Margarine
and self-limited condition that usually resolves without intervention
• Salad dressings
by 3-4 years of age. Parents should be reassured and encouraged to
• Liquid and powdered milk-based meal replacements
place the child on a regular, unrestricted diet to provide adequate calo-
• Protein powders and bars
ries. The diarrhea often improves with removal of prior dietary restric-
• Candies
tions and by limiting fruit juice intake. Some patients may improve
• Nondairy liquid and powdered coffee creamers
with increasing the fat content of the diet (e.g., switching from low fat
• Nondairy whipped toppings
milk to whole milk), which can slow gastrointestinal transit time.
• Certain medications
If a food label includes any of the following words, the product contains Small Intestinal Bacterial Overgrowth (SIBO)
lactose: The normal small intestine is colonized with relatively few bacteria,
• Milk typically less than 104 organisms/mL. Various conditions such as short
• Lactose bowel syndrome, malnutrition, pseudo-obstruction, bowel strictures,
• Whey and achlorhydria from medications such as proton pump inhibitors
• Curds may result in overgrowth of aerobic and anaerobic bacteria in the
• Milk by-products small bowel. Symptoms of abdominal pain, bloating, abdominal dis-
• Dry milk solids tention, and diarrhea arise as bile acids are deconjugated and fatty
• Nonfat dry milk powder acids are hydroxylated by bacteria, leading to an osmotic diarrhea.
From National Digestive Diseases Information Clearinghouse. Lactose The diagnosis can be made by breath hydrogen testing showing early
intolerance. <http://digestive.niddk.nih.gov/ddiseases/pubs/ and late rise in breath hydrogen after ingestion of lactulose. Quantita-
lactoseintolerance>; 2015. tive jejunal aspirate cultures showing greater than 105 organisms/mL
TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea

Pathophysiology and Known
Disorder Genetic Associations Characteristic Signs and Symptoms Diagnostic Evaluation
Disorders of Absorption and Transport of Nutrients and Electrolytes

Congenital chloride AR, SLC26A3 Profuse secretory diarrhea Clinical features
diarrhea Alterations in the intestinal Cl−/ Acidic stools Molecular genetic testing
HCO3− exchanger Hypochloremic, hypokalemic metabolic alkalosis
Fecal chloride concentration >90 mmol/L
Congenital sodium AR, SPINT2 Profuse watery secretory diarrhea Clinical features
diarrhea Impaired jejunal Na+/H+ exchange due to High fecal sodium losses Molecular genetic testing
the reduced activity of serine Alkaline stools
peptidase inhibitor, Kunitz type 2 Hyponatremic, hypokalemic metabolic acidosis
Acrodermatitis AR, SLC39A4 Presents around the time of weaning from breast Clinical features
enteropathica Impaired duodenal and jejunal zinc milk (0-9 mo of age in formula-fed infants) Molecular genetic testing
transport Very severe perioral and perianal rash
Improvement in rash within 3 wk of oral zinc
supplementation
Lysininuric protein AR, SLC7A7 Presents around the time of weaning Clinical features
intolerance Impaired amino acid transport due to Recurrent vomiting with episodes of diarrhea Elevated ammonia after a protein-
altered light chain of the solute carrier Episodes of stupor and coma after a protein-rich rich meal
family 7, member 7 meal Abnormal urine and serum amino
Poor feeding acid profile
Aversion to protein-rich food Molecular genetic testing
Failure to thrive
Enlargement of the liver and spleen
Muscular hypotonia
Chylomicron retention AR, SAR1B Vomiting, osmotic diarrhea, and failure to thrive Low cholesterol levels and normal
disease Impaired chylomicron transport within triglycerides
enterocytes owing to the altered Low fat-soluble vitamins, in
activity of a small GTPase particular vitamin E
Endoscopy: lipid accumulation in
enterocytes
Abetalipoproteinemia AR, MTTP Presents in the first few months of life with FTT, Low cholesterol, low triglycerides,
Impaired microsomal triglyceride transfer diarrhea, and steatorrhea absent apolipoprotein B
protein activity, lower synthesis of Fat-soluble vitamin deficiency Acanthosis of red blood cells
VLDL and reduced absorption of lipids Hypotonia, abnormal gait
Retinitis pigmentosa
Primary bile acid AR, SLC10A2 Presents in the first few months of life with SeHCAT test with a selenium-labeled
diarrhea Reduced enterohepatic reabsorption of secretory diarrhea and failure to thrive bile acid. Retention <10% after 7
bile acids by solute carrier family 10, Diarrhea worse with fatty foods days is diagnostic
member 2 Stool bile acid measurement
Familial diarrhea AD, GUCY2C Early-onset chronic secretory diarrhea, abdominal Molecular genetic testing
syndrome Increased activity of guanylate cyclase distention and bloating
2C enhances levels of cGMP, Subset of patients with inflammatory bowel
hyperactivating intestinal cystic fibrosis disease and irritable bowel syndrome
transmembrane conductance regulator
Diarrhea-associated AR, DGAT1 Infantile-onset chronic diarrhea and protein-losing Molecular genetic testing
DGAT1 mutation Impaired activity of diacylglycerol enteropathy
O-acyltransferase
Defects in Enterocyte Structure

Congenital tufting AR: EPCAM (defective activity of Presents in the first few months of life with Endoscopy: blunted villi and
enteropathy epithelial cell adhesion molecule chronic watery diarrhea and impaired growth characteristic focal epithelial
causes altered cell–cell adhesion) Some patients have superficial punctate keratitis “tufts” composed of closely packed
AR: SPINT2 (impaired activity of serine and choanal atresia enterocytes with rounding of the
peptidase inhibitor, Kunitz type 2, apical plasma membrane that
which is involved in epithelial results in a teardrop configuration
regeneration) of the affected epithelial cell
Molecular genetic testing
Continued
TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea—cont’d

Microvillus inclusion AR: MYO5B (reduced activity of myosin Neonatal-onset chronic unremitting diarrhea On higher magnification, the surface
disease 5B causes abnormal recycling of Some develop cholestatic liver disease that enterocytes are focally piled-up
endosomes) worsens after intestinal transplantation and disorganized, with extensive
AR: STX3 (impaired activity of syntaxin vacuolization of the apical
3, which is involved in membrane cytoplasm and loss of brush border
fusion of apical vesicles) definition
On periodic acid–Schiff (PAS)
staining of the apical brush border
is poorly defined and there is
PAS-positive staining of the apical
cytoplasm of enterocytes
Molecular genetic testing
Trichohepatoenteric AR: TTC37 (impaired synthesis or Chronic infantile diarrhea, facial dysmorphism, Moderate to severe villus atrophy
syndrome (syndromic localization of brush border and hair abnormalities. Other associated with inconstant infiltration of
diarrhea) transporters due to the reduced symptoms: IUGR, immunodeficiency, skin mononuclear cells
activity of tetratricopeptide repeat abnormalities, liver disease, congenital cardiac Molecular genetic testing
domain 37) defects, and platelet anomalies
AR: SKIV2L (unknown mechanism due to
the impaired activity of SKI2W
helicase)
Neuro-Enteroendocrine Diarrhea
Enteric anendocrinosis AR, NEUROG3 Severe secretory diarrhea in infancy Molecular genetic testing
Altered neurogenin-3, which regulates Insulin-dependent diabetes mellitus in childhood
the development of gut epithelial cells
into endocrine cells
Mitchell-Riley AR, RFX6 Malabsorptive diarrhea Molecular genetic testing
syndrome Reduced activity of regulatory factor X6 Duodenal atresia and biliary abnormalities
involved in pancreatic morphogenesis Neonatal diabetes mellitus
and development
X-linked lissencephaly X-linked, ARX Mental retardation, seizures, lissencephaly, Molecular genetic testing
and mental Impaired activity of aristaless related abnormal genitalia
retardation homeobox transcriptional factor, which Occasionally congenital diarrhea
regulates enteroendocrine cell
development
Defects in Intestinal Immune-Related Homeostasis

Eosinophilic Various causes, including food allergies Diarrhea, blood in stools, low albumin, anemia Endoscopic mucosal biopsies
gastroenteritis and (cow’s milk protein), medications, showing more than normal
colitis infections (e.g., Helicobacter pylori), eosinophilic infiltration
immune dysregulation disorders, and
idiopathic
Early-onset AR, mutations of IL-10 or its receptors, Enterocolitis with ulcerative lesions in the Lack of STAT3 phosphorylation in
enteropathy with IL10RA and IL10RB. Altered IL-10 or its perianal area and in the intestinal mucosa. response to IL-10
colitis receptor subunits involved in the Most present during the first 6 mo of life Molecular genetic testing
control of intestinal microbial Folliculitis
stimulations
IPEX syndrome X-linked, FOXP3 mutation Severe neonatal-onset inflammatory diarrhea Flow cytometry might show
Impaired activity of forkhead box P3 Eczematous skin rash decreased peripheral FOXP3+
involved in the development of Endocrinopathy (infantile diabetes mellitus) regulatory T cells
CD4+CD25+ regulatory T cells Peripheral eosinophilia and increased serum IgE Molecular genetic testing
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia and neutropenia
TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea—cont’d

IPEX-like disorders AR: Il2RA (impaired synthesis of α chain Presentation similar to IPEX Molecular genetic testing
of IL-2 receptor on regulatory T cells)
AR: STAT5B (impaired activity of STAT5B
involved in IL-2 signaling in regulatory
T cells)
AD: STAT1 (enhanced or reduced activity
of STAT1 causes the reprogramming of
regulatory T cells into Th1-like cells)
AR: ITCH (altered activity of itchy E3
ubiquitin protein ligase implicated in
the development of regulatory T cells)
AR: LRBA (impaired activity of
lipopolysaccharide-responsive
beige-like anchor protein stimulates
apoptosis of regulatory T cells)
Pancreatic Insufficiency
Cystic fibrosis AR, Mutations involving CFTR. More Meconium ileus in neonate Low stool elastase
than 1300 mutations have been Megacolon High sweat chloride (>60 mEq/L)
described. Most common is ΔF508 Chronic diarrhea from pancreatic insufficiency Newborn screening
mutation starting from 1 mo of age Molecular genetic testing
Failure to thrive
Conjugated hyperbilirubinemia
Shwachman-Diamond AR Chronic diarrhea from pancreatic insufficiency Clinical features
syndrome SBDS gene in over 90% Bone marrow failure Molecular genetic testing
Skeletal changes
Pancreatic lipomatosis on diagnostic imaging
(ultrasound or computed tomography)
Johanson-Blizzard AR Chronic diarrhea from pancreatic insufficiency Clinical features
syndrome UBRI gene Dysmorphic features: aplastic alae nasi, extension Molecular genetic testing
of the hairline to the forehead with upswept
frontal hair, low-set ears, large anterior
fontanel, micrognathia, thin lips, microcephaly,
aplasia cutis (patchy distribution of hair with
areas of alopecia), dental anomalies, poor
growth, and anorectal anomalies (mainly
imperforate anus)
Pearson syndrome Sporadic: caused by de novo single, Chronic diarrhea from pancreatic insufficiency Clinical features
large deletions of mtDNA, which can Sideroblastic anemia, variable neutropenia, Molecular genetic testing
range from 1000 to 10,000 nucleotides thrombocytopenia, and vacuolization of bone
marrow precursors
Lactic acidosis and liver failure
AD, autosomal dominant; AR, autosomal recessive; cGMP, cyclic guanosine monophosphate; IUGR, intrauterine growth restriction; IgE,
immunoglobulin E; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; SeHCAT, selenium homocholic acid taurine; STAT3,
signal transducer and activator of transcription 3; IL, interleukin; mtDNA, mitochondrial DNA; VLDL, very low density lipoprotein.
are suggestive of SIBO, although established cutoff ranges and specific- and bloating or distention. Diagnosis requires that patients have a
ity are imperfect. normal physical examination and growth curve and meet both of the
following criteria at least once per week for at least 2 months before
Irritable Bowel Syndrome (IBS) diagnosis:
Irritable bowel syndrome is characterized by recurrent abdominal pain 1. Abdominal discomfort (an uncomfortable sensation not described
and altered bowel habits that typically presents in adolescence. Symp- as pain) or pain associated with 2 or more of the following at least
toms include abnormal stool frequency (either 4 or more stools per 25% of the time:
day, or 2 or fewer stools per week), abnormal stool form (either loose a. Improvement with defecation
and watery or lumpy and hard), abnormal passage of stool (e.g., strain- b. Onset associated with a change in frequency of stool
ing, urgency, feeling of incomplete evacuation), the passage of mucus, c. Onset associated with a change in form (appearance) of stool
2. No evidence of an inflammatory, anatomic, metabolic, or neoplas- an inflammatory enteropathy characterized by villous atrophy, elon-
tic process that explains the subject’s symptoms gated crypts, and intraepithelial lymphocytosis.
The etiology and pathogenesis of irritable bowel syndrome are not Celiac disease symptoms are protean and reflect its systemic nature.
well understood. Visceral hypersensitivity has been well documented The age of onset is variable and a high degree of suspicion is needed.
in children with IBS. Genetic predisposition, early stressful events, and Manifestations include recurrent abdominal pain, nausea and vomit-
ineffective coping mechanisms are compounding factors. Additional ing, iron deficiency with or without anemia, short stature, aphthous
mechanisms may include infection, inflammation, intestinal trauma, stomatitis, chronic fatigue, arthritis, raised aminotransferase levels,
allergy, and disordered gut motility. and reduced bone mineral density. Rare manifestations include ataxia,
dermatitis herpetiformis, which is a blistering rash with pathogno-
Celiac Disease monic cutaneous IgA deposits, and celiac crisis, which is a rare life-
Celiac disease is an immune-mediated systemic disorder elicited by threatening syndrome mostly observed in children, that is characterized
exposure to gluten and related proteins in genetically susceptible indi- by severe diarrhea, hypoproteinemia, and metabolic and electrolyte
viduals. Clinical presentations vary, although the hallmarks of celiac imbalances. The classic presentation of a toddler with chronic diarrhea,
disease include enteropathy and the presence of disease-specific anti- abdominal distention, and failure to thrive is uncommon. Most
bodies. Prevalence is as high as 1% in Western nations, with most patients are identified via serologic screening in the context of a strong
affected individuals presenting in childhood. A genetic predisposition family history or other risk factors.
is suggested by familial aggregation and the high concordance in Serological tests are the cornerstone of screening for celiac disease
monozygotic twins, which approaches 100%. A strong association with in patients with risk factors or a suggestive history (Table 11.16). Estab-
human leukocyte antigen (HLA)-DQ2.5, and to a lesser degree HLA- lishing the diagnosis is dependent on the levels of disease-specific
DQ8, has been identified. A family or personal history of autoimmune antibodies detected. Total serum IgA should be obtained to exclude
disease and certain genetic conditions confers a higher risk (Table IgA deficiency. If total serum IgA is normal and anti-tissue transglu-
11.15). taminase IgA antibodies are negative, celiac disease is unlikely. Patients
The pathogenesis of celiac disease first involves exposure to gliadin, with positive anti-tissue transglutaminase IgA antibodies that are less
a protein component of wheat gluten, or structurally related storage than 10 times the upper limit of normal should undergo upper endos-
proteins (prolamines) found in rye and barley. Altered processing by copy with multiple biopsies. If biopsies demonstrate total or partial
intraluminal enzymes, changes in intestinal permeability, and activa- villous atrophy, elongated crypts, and increased intraepithelial
tion of the innate immune response precede the development of an lymphocytes (>25 lymphocytes/100 enterocytes), the diagnosis is
adaptive immune response that results in systemic autoimmunity and confirmed. Patients with positive anti-tissue transglutaminase IgA
antibodies that are greater than or equal to 10 times the upper limit of
normal should have anti-endomysial IgA antibodies and HLA testing
performed. If the patient is positive for anti-endomysial IgA antibodies
and is positive for DQ2 or DQ8 HLA testing, the diagnosis is con-
TABLE 11.15 Conditions Whose Presence firmed; if either or both are negative, the patient should undergo
Confers a Higher Risk of Celiac Disease biopsy.
Patients with celiac disease experience relief in their symptoms
Incidence of Celiac
when placed on a strict gluten-free diet. Complications associated with
Condition Disease (%)
untreated celiac disease include osteoporosis, impaired splenic func-
First-degree relative with celiac disease 2-20 tion, neurologic disorders, infertility or recurrent abortion, ulcerative
Type 1 diabetes mellitus 3-12 jejunoileitis, and cancer. Enteropathy-associated T-cell lymphoma
Juvenile idiopathic arthritis 1.5-2.5 and adenocarcinoma of the jejunum are rare complications of celiac
Down syndrome 0.3-5.5 disease. Refractory celiac disease is diagnosed when there are persis-
tent or recurrent malabsorptive symptoms and signs of villous atrophy
Turner syndrome 6.5
on biopsy despite strict adherence to a gluten-free diet for more than
Williams syndrome 9.5
12 months. Refractory celiac disease can be classified as type 1 (char-
IgA nephropathy 4 acterized by the presence of normal intraepithelial lymphocytes), or
IgA deficiency 3 type 2 (characterized by abnormal intraepithelial lymphocytes; clonal
Autoimmune thyroid disease 3 intraepithelial lymphocytes lacking surface markers CD3, CD8, and
Autoimmune liver disease 13.5 T-cell receptors; or both). Type 2 refractory celiac disease is associated
with a higher risk of ulcerative jejunoileitis and lymphoma.
TABLE 11.16 Serologic Tests for Celiac Disease

Test Sensitivity (Percent) Specificity (Percent) Comments
Anti-tissue transglutaminase IgA >95 (73-100) >95 (77-100) Recommended screening test
Anti-tissue transglutaminase IgG Widely variable (12.6-99.3) Widely variable (86.3-100) Useful in patients with IgA deficiency
Anti-endomysial antibody IgA >90.0 (82.6-100) 98.2 (94.7-100) Useful in patients with an uncertain
diagnosis. Expensive.
Anti-deamidated gliadin peptide IgG >90.0 (80.1-98.6) >90.0 (86.0-96.9) Useful in patients with IgA deficiency
and young children
IgA, immunoglobulin A; IgG, immunoglobulin G.
Inflammatory Bowel Disease (IBD) TABLE 11.17 Clinical Manifestations of

Inflammatory bowel disease is divided broadly into ulcerative colitis
Inflammatory Bowel Disease
and Crohn disease, idiopathic systemic chronic inflammatory diseases Manifestation Comments
whose primary symptoms are related to relapsing gastrointestinal
tract inflammation. Common signs and symptoms include diarrhea, Gastrointestinal
abdominal pain, blood in the stools, and nutritional compromise. Diarrhea with or without blood Isolated small bowel Crohn disease
Ulcerative colitis consists of mucosal inflammation restricted to the may not manifest with diarrhea
colon, while Crohn disease consists of transmural inflammation that or grossly bloody stools
affects all layers of the intestinal wall and may involve any portion of Abdominal pain
the gastrointestinal tract from the mouth to the anus. Ulcerative colitis Hematochezia More common in ulcerative colitis
involves the colon in a continuous fashion, typically starting in the Anorexia, weight loss, and fatigue More common in Crohn disease
rectum and extending proximally to variable degrees. Crohn disease is
Growth failure and pubertal delay More common in Crohn disease
characterized by skip lesions, in which there are areas of normal-
appearing mucosa interspersed with inflammatory lesions. Abdominal mass Only in Crohn disease
The prevalence of ulcerative colitis is as high as 246 per 100,000 Fever and night sweats More common in Crohn disease
persons, and the prevalence of Crohn disease is as high as 199 per Vomiting and nausea Seen in both but severe would
100,000 persons. Approximately 25% of all IBD is diagnosed in chil- suggest intestinal obstructive
dren and adolescents, although presentation prior to 6 years of age is process from Crohn disease
rare.
Clinical presentation. Up to 80% of children with Crohn disease Extraintestinal
will present with diarrhea. Stool may contain microscopic blood, Iritis and uveitis More common in Crohn disease
although may not be grossly bloody, especially in the absence of sig- Aphthous ulceration More common in Crohn disease
nificant left-sided colonic disease. Diarrhea is more common in colonic Erythema nodosum More common in Crohn disease
disease and may be absent altogether in cases of isolated small bowel
Pyoderma gangrenosum More common in ulcerative colitis
inflammation. In ulcerative colitis, diarrhea is a more consistent pre-
senting feature, often insidious in its development but eventually pro- Musculoskeletal
gressing to hematochezia. Nocturnal diarrhea with urgency may be a • Axial arthropathy and ankylosing
sign of left-sided colonic inflammation in both entities. Gastro- spondylitis
intestinal and extraintestinal manifestations otherwise vary between • Polyarticular arthritis
Crohn disease and ulcerative colitis (Table 11.17). Extraintestinal man- • Pauciarticular arthritis
ifestations are present in up to 23% of children at diagnosis, with a • Osteoporosis
higher frequency in those over 6 years of age. Liver
Physical examination should establish nutritional status and • Primary sclerosing cholangitis
include an assessment of growth parameters, including the review • Autoimmune hepatitis and
of previous growth charts. Pubertal status should also be recorded. overlap syndrome
Oral cavity examination should look for aphthous ulcers that are • Cholelithiasis
present in approximately 10% of IBD patients (more commonly in Autoimmune pancreatitis
Crohn disease). An eye examination should look for episcleritis, Cardiovascular
painful inflammation of the outer layer of the sclera, and patients • Myocarditis
with known IBD should be followed by an ophthalmologist to assess • Pericarditis
for uveitis and keratopathy. A detailed abdominal examination should
Pulmonary Crohn disease Commonly involves large airways,
document abdominal distention, mass, tenderness and hyper- or
but parenchymal disease, such as
hypoactive bowel sounds. Particular attention should be paid to
organizing pneumonia, interstitial
assessing the perianal region for any abscesses or fistulas. Skin exami-
disease, and necrobiotic nodules,
nation should look for erythema nodosum, painful raised red lesions
has been described
about 1-3  cm in diameter typically found on the shins; pyoderma
gangrenosum, a severe ulcerating rash; and psoriatic lesions. Two Renal More common in Crohn disease
clinical features suggest a diagnosis of Crohn disease over ulcerative • Nephritis compared to ulcerative colitis
colitis: the presence of perianal disease and the presence of structur- • Amyloidosis
ing and fistulizing disease of the bowel. No other systemic or extrain- • Urolithiasis (especially oxalate
testinal manifestations reliably suggest one diagnosis over the other stones)
(Table 11.18). Hematologic
Diagnosis. IBD is a clinical diagnosis that integrates history and • Iron-deficiency anemia, anemia of
physical findings with objective data from imaging studies, labora- chronic disease, vitamin B12
tory evaluation, and endoscopic findings including histopathology. deficiency or folate deficiency
Diagnosis should neither be confirmed nor excluded on any one • Immune thrombocytopenia
variable or result: up to 54% of patients with mild ulcerative colitis • Deep vein thrombosis
and 21% of patients with mild Crohn disease have normal hemo-
globin, albumin, CRP, and ESR levels at the time of initial diagnosis.
Important mimics of IBD include irritable bowel syndrome, Behçet
disease, infectious enterocolitis (particularly enterovirus and Yersinia),
TABLE 11.18 Comparison of Crohn Disease and Ulcerative Colitis

Feature Crohn Disease Ulcerative Colitis
Malaise, fever, weight loss Common Common
Rectal bleeding Sometimes Usual
Abdominal mass Common Rare
Abdominal pain Common Common
Perianal disease Common Rare
Ileal involvement Common None (backwash ileitis)
Strictures Common Unusual
Fistula Common Very rare
Skip lesions Common Not present
Transmural Involvement Usual Not present
Crypt abscesses Variable Usual
Intestinal granulomas Common Rarely present
Risk of cancer* Increased Greatly increased
Erythema nodosum Common Less common
Mouth ulceration Common Rare
Osteopenia at onset Yes No
Autoimmune hepatitis Rare Yes
Sclerosing cholangitis Rare Yes
*Colonic cancer, cholangiocarcinoma, lymphoma in Crohn disease.

From Bishop WP, Ebach DR. Intestinal tract. In: Marcdante KJ, Kliegman RK, eds. Nelson Essentials of Pediatrics. 7th Edition. Philadelphia:
Saunders; 2015:437-444.
TABLE 11.19 Differential Diagnoses of Presenting Symptoms of Crohn Disease

Primary Presenting Symptom Differential Diagnosis
Right lower quadrant abdominal pain, with or without mass Appendicitis, infection (e.g., Campylobacter, Yersinia species, tuberculosis or atypical
mycobacteria), lymphoma, intussusception, mesenteric adenitis, Meckel
diverticulitis, ovarian cyst or ovarian torsion, ectopic pregnancy
Chronic periumbilical or epigastric abdominal pain Irritable bowel syndrome, constipation, lactose intolerance, peptic ulcer disease,
functional dyspepsia
Rectal bleeding, no diarrhea Fissure, polyp, Meckel diverticulum, solitary rectal ulcer syndrome
Bloody diarrhea Infection, allergic colitis, hemolytic uremic syndrome, Henoch-Schönlein purpura,
ischemic bowel, radiation colitis
Watery diarrhea Irritable bowel syndrome, lactose intolerance, giardiasis, Cryptosporidium infection,
sorbitol, laxatives
Perirectal disease Fissure, hemorrhoid (rare), streptococcal infection, condyloma (rare)
Growth delay Endocrinopathy
Anorexia, weight loss Celiac disease, other systemic illnesses, anorexia nervosa
Arthritis Collagen vascular disease, infection
Liver abnormalities Chronic hepatitis
Oral ulcers Celiac disease
and tuberculosis (Tables 11.19 and 11.20). As such, every patient underlying immune dysregulation disorder as an additional mimic
with a history and examination suggestive of IBD should have stool of IBD (Table 11.21). Stool biomarkers such as calprotectin and
studies for infectious organisms and special request should be made lactoferrin should be utilized to exclude non-inflammatory causes
for Yersinia culture if multiplex PCR assays that include Yersinia before considering endoscopic procedures. The suggested diagnostic
testing are not available. Patients presenting with suggestive symp- evaluation of suspected inflammatory bowel disease is presented in
toms prior to 6 years of age may require an evaluation for an Table 11.22.
TABLE 11.20 Infectious Agents Mimicking Inflammatory Bowel Disease

Agent Manifestations Diagnosis Comments
Bacteria
Campylobacter jejuni Acute diarrhea, fever, fecal blood and leukocytes Culture or nucleic acid Common in adolescents, may relapse
amplification assay
Yersinia enterocolitica Acute diarrhea that can become chronic, right lower Culture or nucleic acid Common in adolescents as fever of
quadrant pain, mesenteric adenitis– amplification assay unknown origin, weight loss,
pseudoappendicitis, fecal blood and leukocytes abdominal pain
Extraintestinal manifestations may mimic Crohn
disease
Clostridium difficile Onset during or following a course of antibiotics, Cytotoxin assay or nucleic May be nosocomial
watery → bloody diarrhea, pseudomembrane on acid amplification assay Toxic megacolon possible
sigmoidoscopy
Escherichia coli O157:H7 Colitis, fecal blood, abdominal pain Culture and typing or Hemolytic uremic syndrome possible
nucleic acid amplification
assay
Salmonella Watery → bloody diarrhea, foodborne, fecal Culture or nucleic acid Usually acute
leukocytes, fever, pain, cramps amplification assay
Shigella Watery → bloody diarrhea, fecal leukocytes, fever, Culture or nucleic acid Dysentery symptoms
pain, cramps amplification assay
Edwardsiella tarda Bloody diarrhea, cramps Culture Ulceration on endoscopy
Aeromonas hydrophila Cramps, diarrhea, fecal blood Culture May be chronic
May be acquired from contaminated
drinking water or swimming in
contaminated pools or freshwater
sources
Plesiomonas shigelloides Diarrhea, cramps Culture Shellfish source
Tuberculosis Rarely bovine, now Mycobacterium tuberculosis Culture, purified protein Can mimic Crohn disease
Ileocecal area, fistula formation derivative, biopsy,
interferon gamma release
assay
Parasites
Entamoeba histolytica Acute bloody diarrhea and liver abscess, colic Trophozoite in stool, Travel to endemic area
colonic mucosal flask
ulceration, serologic tests
Giardia lamblia Foul-smelling, watery diarrhea, cramps, flatulence, “Owl”-like trophozoite and May be chronic
weight loss; no colonic involvement cysts in stool; rarely
duodenal intubation
Opportunistic Organisms in the Setting of Immune Deficiency

Cryptosporidium Chronic diarrhea, weight loss Stool microscopy Mucosal findings not like
inflammatory bowel disease
Isospora belli Chronic diarrhea, weight loss Stool microscopy Tropical location
Cytomegalovirus Colonic ulceration, pain, bloody diarrhea Culture, biopsy More common when on
immunosuppressive medications
From Grossman AB, Baldassano RN. Chronic ulcerative colitis. In: Kliegman RM, Stanton BF, St. Geme JW III, Schor NF, eds. Nelson Textbook
of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016:1823.
TABLE 11.21 Chronic Inflammatory-Like Intestinal Disorders Including Monogenetic Diseases

Infection (See Table 11.20) Vascular–Ischemic Disorders
Idiopathic Pathogen-Negative AIDS Enteropathy Systemic vasculitis (systemic lupus erythematosus, dermatomyositis)
Immune–Inflammatory Henoch-Schönlein purpura
Severe combined immunodeficiency Hemolytic uremic syndrome
Agammaglobulinemia Granulomatosis with angiitis
Chronic granulomatous disease
Other
Wiskott-Aldrich syndrome
Glycogen storage disease type 1b
Common variable immunodeficiency
Dystrophic epidermolysis bullosa
Acquired immunodeficiency
X-linked ectodermal dysplasia and immunodeficiency
Dietary protein enterocolitis
Dyskeratosis congenita
Polyglandular autoimmune syndrome type 1
ADAM-17 deficiency
Behçet disease
Prestenotic colitis
Lymphoid nodular hyperplasia
Diversion colitis
Eosinophilic gastroenteritis
Radiation colitis
Omenn syndrome
Neonatal necrotizing enterocolitis
Graft-versus-host disease
Typhlitis
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
Sarcoidosis
syndrome
Hirschsprung colitis
Interleukin-10 signaling defects
Intestinal lymphoma
Autoimmune enteropathy*
Laxative abuse
Microscopic colitis
Endometriosis
Hyperimmunoglobulin M syndrom
Hermansky-Pudlak syndrome
Hyperimmunoglobulin E syndrome
Trichohepatoenteric syndrome
Mevalonate kinase deficiency
PTEN hamartoma syndrome
Familial Mediterranean fever
Phospholipase Cγ2 defects
Familial hemophagocytic lymphohistiocytosis type 5
X-linked lymphoproliferative syndromes types 1, 2
Congenital neutropenias
Leukocyte adhesion deficiency 1
*May be the same as IPEX.
From Grossman AB, Baldassano RN. Chronic ulcerative colitis. In: Kliegman RM, Stanton BF, St. Geme JW III, Schor NF, eds. Nelson Textbook
of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016:18, Table 336-5.
TABLE 11.22 Suggested Evaluation in Suspected Inflammatory Bowel Disease

Test Common Abnormalities/Comments
Complete blood count with differential Anemia, especially iron deficiency
Comprehensive metabolic panel Hypoalbuminemia, elevated liver enzymes, low alkaline phosphatase (likely secondary to associated
zinc deficiency)
Erythrocyte sedimentation rate Elevated in CD > UC
C-reactive protein Elevated in CD > UC
Stool cultures with Yersinia; ova and parasites Always rule out infectious causes as the likely reason for symptoms
Clostridium difficile toxin assay or polymerase chain Could be an isolated reason for symptoms or could be a superimposed illness
reaction assay
Fecal occult blood Positive in vast majority of patients. No need for this test if patient has grossly bloody stools
Fecal calprotectin (or lactoferrin) To distinguish inflammatory bowel disease from irritable bowel syndrome (IBS) prior to considering
invasive procedures such as enodoscopy
Esophagogastroduodenoscopy and ileocolonoscopy After ruling out other causes of patient’s symptoms
Imaging studies Consider for evaluation of patients presenting with fistulizing or structuring disease. Also used for
• MRI and MR-enterography (MRE) evaluation of small bowel after endoscopic procedures
• CT abdomen
• Abdominal ultrasound
Wireless capsule endoscope Consider for evaluation of small bowel in very young children in whom MRE is difficult or in
situations where conventional endoscope and imaging tools have been nondiagnostic
CD, Crohn disease; CT, computed tomography; MRI, magnetic resonance imaging; UC, ulcerative colitis.
SUMMARY AND RED FLAGS

Acute diarrhea is a common childhood illness. For most children, the risk of dehydration, as are 10 or more stools a day and frequent emesis
etiologic agent is of no therapeutic significance. Exceptions are giardia- and fever.
sis, pseudomembranous colitis, dysentery suggestive of Shigella infec- Chronic diarrhea may be benign or may signify a more serious
tion, amebiasis, or Campylobacter infection, all of which necessitate illness associated with malabsorption, inflammation, or congenital
specific treatment. Oftentimes of greater importance are the secondary defects. Red flags include onset of diarrhea in the neonatal period,
complications associated with fluid and electrolyte losses and the weight loss, growth stunting, anorexia, fever, fatty stools, blood in
reduced oral fluid intake, which may result in shock and its systemic stools, extraintestinal manifestations associated with intestinal disease,
complications. history of travel to countries with poor sanitation and water supply,
Red flags for acute diarrhea are the manifestations of dehydration and specific nutritional deficiencies associated with malabsorption.
(see Table 11.6). Young age (<6 months) is associated with a greater
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11

TABLE 11.1 Differential Diagnosis of Acute and Chronic Diarrhea by Age

TABLE 11.3 Distinguishing Isolated Carbohydrate from Isolated Fat Malabsorption

TABLE 11.4 Differential Diagnosis of TABLE 11.5 Causes of Acute

Vomiting is the Diarrhea is the

Watery Diarrhea with

• Staphylococcus aureus (dairy, produce, • Clostridium perfringens • Nontyphoidal salmonellosis

TABLE 11.6 Assessment of Degree of Dehydration

TABLE 11.7 Complications of Bacterial Enteric Infections

Parasitic Diarrhea TABLE 11.8 Medications and Substances

Other Causes of Acute Diarrhea CHRONIC DIARRHEA

TABLE 11.9 Foodborne Gastrointestinal Illnesses

TABLE 11.9 Foodborne Gastrointestinal Illnesses—cont’d

*Potentially dangerous; observation in hospital often required.

immunodeficiency should be documented. Family history should

CHRONIC DIARRHEA IN INFANTS <6 MONTHS OF AGE

Stool culture Weight loss or poor weight gain

Abnormal Normal Stool studies for: Consider:

Postinfectious enteritis Postinfectious

CHRONIC DIARRHEA IN INFANTS >6 MONTHS OF AGE ( >2 WEEKS’ DURATION)

Bacterial gastroenteritis Consider: Excessive juice (sorbitol) intake

4. Reduced maltase activity

TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea

Disorders of Absorption and Transport of Nutrients and Electrolytes

Defects in Enterocyte Structure

TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea—cont’d

Defects in Intestinal Immune-Related Homeostasis

TABLE 11.14 Disorders Leading to Early-Onset Chronic Diarrhea—cont’d

TABLE 11.16 Serologic Tests for Celiac Disease

Inflammatory Bowel Disease (IBD) TABLE 11.17 Clinical Manifestations of

TABLE 11.18 Comparison of Crohn Disease and Ulcerative Colitis

*Colonic cancer, cholangiocarcinoma, lymphoma in Crohn disease.

TABLE 11.19 Differential Diagnoses of Presenting Symptoms of Crohn Disease

TABLE 11.20 Infectious Agents Mimicking Inflammatory Bowel Disease

Opportunistic Organisms in the Setting of Immune Deficiency

TABLE 11.21 Chronic Inflammatory-Like Intestinal Disorders Including Monogenetic Diseases

TABLE 11.22 Suggested Evaluation in Suspected Inflammatory Bowel Disease

SUMMARY AND RED FLAGS

REFERENCES Bröer S. Lysinuric protein intolerance: One gene, many problems. Am J

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