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Chronic Diarrhea James P. Keating P ediatr. Rev. 2005 ;26;5 -l 4 DOI: I 0. I 5 42lpir.26-l-5
The online version of this article, along with updated information and services, is located on the World Wide Web at: http :i.peclsinreview.aappublications.orglcgi,'cuntentltirlf'26i 1 5 1
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, l4l Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright O 2005 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0l9l-9601. Online ISSN: 1526-3347.
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Article
James P. Keating, MD-
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Eescribe how
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fharacterize the causes
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prevent intractable diarrhea af infan*y"
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chrsnic, acquired diarrhea.
the severe, rare congenital diarrheas. factitious rJiarrhea and its signs anel syrnptoms.
Recogniee and diagnose Discuss
lntroduction Although this review States
fbcuses
primarily on issues that a pediatric practitioner in the United
or Canada may need to consider when faced with a patient rvho has protracted
diarrhea, rve should not ignorc the role that Nord-r American pediatric practices play in
world health. The harm done within and beyond our borders bv the once common practices oflr'ithdrawing or diluting the feedings ofinfurts rvho had diarrhea and overusing intravenotts hvdration ancl bottle -tbeding have vet to be corrected fully. Implementation of
the core concepts contained in the American Academy of Pediatrics (AAP) Practice Paranteter fbr Acute Gastroenteritis (1996) is incomplete, although much progress has been rnade. Recurrent, chronic, infantile diarrhea, acting in concert vl'ith n.ralmrtrition, causes the death of 4.6 million children global\' each 1,ear. Prolonged diarhea is a threat to life rvhenever or r,vherever safe food and lvater are not provided due to inadequate supply, ip;uorance , or malice .'Ihe near elimination of this lethal outcome of diarrhea in the United States and Canada is attributablc, in paft, to the successes of agriculture and public health measllres in the 20th and 2lst centuries that have made food abundant and safer. Also, in the last 25 years, the follor,ving specific preventive measures have reduced further the number of infants who har-e this condition: l) renewed emphasis on breastfeeding, 2) reduction in the use of partial starvation regimens during diarrheal episodes, and 3) increased availability of age-appropriate infant food for children living in poverty (Special Supplemental Food Program for Won'ren, Infants and Children) (!\tIC). In the developing world, the dorvnward spiral of diarrhea and undernutrition often ends in death; in the presence of modern \vestern medical care, the condition usually is revercible, even in its late stages. Once an infant is recognized as having intractable diarrhea of infancy (IDI), enteral therapy with a lactose-fiee, sucrose-free, medium-chain triglyceride tbrmula often allorvs recovery. If entcral therapy fails, parenteral nutrition becomes necessary and curative. Full irnplementation of the AAP guidelines for treatment of acute gastroenteritis and the expansion of dre WIC program to cover all who may benefit eventually should eliminate this potentiallv fatal lbrm ofchronic diarrhea lvithin the United States, although it will reappear whenever understanding of its cause and prel'ention are forgotten.
Definitian No limit ol duration is employed consistently to separate acute and chronic diarrhea. Diarrhea caused by proven or assumed acute infectious agents seldom lasts more than 2 r,veeks, but awareness of the dilibrences in the duration due to the common infectious agents can be useful in identifring patients lvho have more serious problems. 'W. McKim Marriott Professor of Pediatrics; Co-director, Pediatric Residency Program, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Mo.
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thronic diarrhea
Diarrhea in Older Children Many of the entities that cause chronic diarrhea in older children were covered in anclther article in Ped.iatrics in Reviaw (Pietzak and Thornas, 2003 ).
* *}*n**r: r:iti t *i * r r?tt:* CNSD (toddler's diarrhea; IBS, inflnt variant) is a very common condition. The diagnosis is basetl on history and physical examination findings. Often, the primarv care physician successfull,v offers reassurance r.l,ithout making a specific diagnosis. In dre absence of recl flags (Table 9), reassllrance is a good practice. {)* r *rzi
inflamrnation may be misinterpreted as inflammatory bor,vcl disease. Cardiomyopathy from emetine may be misdiagnosed as a svstemic mitochondrial disease.
Diagnosis is difficult. Study of the electroll'te and osmotic composition of feces can reveal the presence of one of the osmotic agents, and emetine can be found in feces, gastric contents, blood, and urine. 'l'hese snrdies
should not be attempted without expert guidance. A carefi:lly maintaincd record of custody of the spccime n from be dside to the final refi;rence lalroratory is needed if the evidence is to hold up against legal challengc. Phenolphthalein u'as rvithdrarvn bv the United States Foo
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VIP concentratioll drops to nonnal fcw days of tumor rescction.
ceases alld the senrm
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ganglioneuroma or ganglioneuroblastoma with a relatively mature cell rype; resectiolt often is cLlrative. 'fhe syndrome also has been reported in metastatic [euroblastoma and has appeared after chemotherapry whsn i1 wxg not present before. The tumor rypically is fbund in an adrenal gland or elsewhere in the retroperitoneal space and occasionally in the mediastinum or neck. The tumor is revealed by computed tornography or conventional radiographs; it mav be calcified. In adults, the syndrome usually is caused by a malignant pancreatic islet cell tumor drat frequently is metastatic at diagnosis. The less common WP-secreting tumors mav be suspected in the presence ofthe cutaneous manifbstations or a family history of an underly'ing syndrome (eg,
neurofibromatosis-1, multiple cndocrine neoplasia I, mastocytoma) associated with those tumors. Intractable diarrhea in patients infectcd with human immunodeficiency vims can be associated rvith a modest elevation of VIP. Improvemcnt after octreotide therapy has been reported in these cases, suggesting that VIP may be causal. I
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is a common complication of a nurnber of immunotlefi-
ciencv states and may be the dominant or prcsenting manifestation in infants. Evaluation of infants who have protracted or life-threatening diarrhea shoulcl inclucic a
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careful family history and a focused phvsical examination that includes the tonsils, lvn,ph nodes, spleen, and skin. Scrutiny of the peripheral blood smear may reveal absence of mature lymphocytcs or polymorphonuclear leukocytes, although more complex analysis often is required. The major immunocleficiencies associated with
chronic diarrhea are listed in Table 8. The course of several of these conditions prescnting in early life is ftilminant and fbtal; life-saving interventions often can be instituted if the diagnosis is considered erarlv. i A{:i i lii}l.Jl l}lAlilthl-4. Intentional poisoning of intants and chilclren *'ith osmotic agents (Epsom salts, magnesium citrate, propylene glycol) and irritants (ipecac, bisacodyl, phenolphthalein) can cause chronic diarrhea, gnrwth arrest, and deadr. The criminal usually is a parent, most often the child's mother. She frequendy is well-informed about the medical diagnostic process and conceals her rolc in creating the illness behind a mask of concern, challenging ev€n the most experienced practitioner's diagnostic abiliq''. This problem is particularly difficult to recognize when superimposed on established medical intervention (eg, central \renous catheter, gastrostomy) or prior proven chronic ilh'ress. Thc clinical characteristics are watery or bloody diarrhea that usually resolves rvhen the patient is admitted to the hospital fbr stucly. Hypokalemia and alkalosis &om chronic loss of potassium and or surreptitious feeding of baking soda may be misinterpreted as eviderrce for a \rlP-secreting tunor. Ipecac poisoning causes diarrhea as lvcll as vomiting, and biopsies at colonoscopy showing
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lvhose onset occurs in the first year after birth. Among the borvel biopsy findings are total villus atrophy and inflammatory cells, including eosinophils, in the epithelium. The condition is distinguished fiom celiac disease b,v the absence of a response to gluten elimination and tiom MVID b,v the absence of inclusions. Nonintestinal immune-mediated problems, such as t,vpc I diabetes,
t:tjt\:t.j"t:i41ii'.L'*tttlt,;,Jillif\t?,111't';t.. Congenitalsoclium cliarrhea is caused by a defect in a jejunal sodium/proton exchange that results in severe watery diarrhea. As in
hypothyroidism, hemolytic anemia, membranous glomerulonephritis, autoimmune hepatitis, and rash, are common. Treatment with prednisone, azathiopritte, c1'clophosphamide, tacrolimus, and prolonged parenteral
tion was described initially by nvo United
States pedia-
tricians.
Treatment consists of providing sulficient salts and \r'ater to replace the diarrheal losses, initially intravenously and later orally. Ifthe diagnosis is made and severe dehydration avoided, grorvth and development often are
CLD, the first manifestations are polyh,rdn*ttios and dilatecl fetal intestine, lvith the onset of diarrhea immeciiately after birth. Only ll patients have been reported. It appears to be an autosornal recessive disease . 'Io date, scarch fbr mutations in the knorvn sodiurr/proton exchanger genes has failed. l:.Jl:i t|1 i::t:4'i1;:11ti?fii'rjT. This disorder presenrs u.ith watery diarrhea in the first weeks after bir-th. The intestinal biopsy reveals focal epithelial "tufts," teardropshaped groups of enterocytcs, and shortening of the microvilli r.vithout inclusions. There is no knou'n effective therapy.
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enteropathica (AE) is characterized by chronic diarrhea, undernutrition, and a rash primarily involving the perioral, perianal, and perineal areas. Semrn zinc and alkaline phosphatase concentrations are lorv, and the signs and symptoms resolve after oral or parenteral zinc therapy. The hereditary fcrrm of AE is rare and follows an auto-
somal recessive pattern. Mutations in a gene (SLC39A4) that encodes a protein that has fbatures characteristic of aZIP zinc transporter have been fcrund in families lvho have dris form ofAE. Zinc supplementa-
nutrition is
associated 'lr.ith an estimated 50% recovery
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fhere have been too ferv patients scattered over too rnan,v years and centers
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trial of immunosuppression regimens. &{any of the
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chronic, high-volume, lvatery diarrhea, hypokalemia, and alkalosis (!1IDHA) syndrome. In the pediatric age range, l- to 3-.vear-olds arc affected most often. Initial misdiagnoses are the comrnon infections, lactose intolerance, or chronic nonspecific diarrhea of infancy (CNSD) and irritable borvel syndrome (IBS). Later in thc course, the secretory nature ofthe diarrhea, persistence of diarrhea during periods of interrupted oral incauses
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serlrm VlP, which is strikingly elevated (eg, 3,2O0 pmol/Lf 90 mEqll [90 mmol/L]) -"y be diagnostic as early as the fourth day after birth. Fecal chloride cal be measured in the hospital laboratory, permitting
cliarrhea or whe rc faculty and trainees devote part of their sen'ice to sites in the developing world.
early diagnosis and therapy. The characteristic hypokalemia rvith metabolic alkalosis also provides an important
for l8 months or longer. Awareness of this increasingly rare entity in the
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diagnostic clue but is prcsent inconsistently when the infant is younger than 6 mondrs of age . CILD is inherited recessively. Clusters occur in Finland, Poland, and the Persian Gulf and in irnmigrants from those areas (l:5,000 in Saudi Arabia). The condiat Hospital For Sick
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but probablv are innocent, transient visitors in those locations. N{etronidazole in a dose of 15 mg/kg for l0 days is the current treatment lbr giardiasis in the United States. Asymptomatic children gcnerally are not treated; screerling of schoolmates or family contacts is uscful only if an epidemiologic study is in process. tlry pr* tSz *r'! 4 i zt r* S:i: rv z; rn This protozoan causes watery tliarrhea that often cotltinues for 2 rveeks and occasionally for longer. The infection results trom ingestion of the organism from fecal contamination of the hands of caretakers, directly from animals, or lrom water in recreational settings. Chlorine is ineffective; the sand filtering necessaq' for removal seldom is carried out at water parks, swimming pools, or petting zoos. Large outbreaks have occurrecl when municipal water supplies are contaminated. Chronic and debilitating diardrea occurs in the immunocompromised host.
The recently introduced combined Giard.iaCryptosp ori diurn fecal antigen tests have better sensitiviq,'
than previous procedures. The diagnosis can be confirmed through microscopic examination of a Kinyoun acid-fast stain of feces, and the organism sometimes is seen in intestinal biopsies. The conventional ova and parasite examination seldom detects this infection. 'fhe incidence of coinfection u,ith Giardia in irnmunocompctent adults is lorv (2%). Diarrfiea caused by both Cryptosporidiwn and Giard.io can be treated u,ith nitazoxanide oral suspension for 3 days.
ficiency, global mucosal dysfunction, and "slick gut" syndrome. Enteric infection and associated compromise ofintake and absorption lead to a variable loss ofdigestive and absorptive capacity in infants. 'Ihe mildest variant of this eft'ect is transient lactose intolerance . In its most severe forrn (IDI), even the least challenging feedings are not tolerated and, if parenteral nutrition is not possible, death occurs. Recurrent episodes of diarrhea ancl failure to regain weight in an infant (usually (6 mo old) should suggest this diagnosis. Suspicion should be raised further by the absence of breastfeeding, the administration ofdiluted or clear liquid feedings, or restriction of intake in a misguidcd effor-t to reduce diarrhea or vomiting. Diagnostic pitfalls abound. Highly absorptive diapers mav rnask the prcsence of waterv diarrhea, even in a hospitalized child. The failure to gain lveight and recurrently low serum bicarbonate concentration in the infant rvho has IDI may result in miscategorization of the condition as renal tubular acidosis, r.r,hich can delay therapy and compromise sun'ival. A delay in diagnosis and intervention until ail alternatives have been ruled out can kill. The practitioner must make the diagnosis and initiate therapy rvithout a positive laboratory or pathologic result. l)iagnosis is based on the physician's awareness of the entity, reasonable exclusion of alternative explanations (Table 5), and el'entually, the patient's response to nntrition therapy and return to full health. Intestinal biopsy findings are nonspecific, and the procedure in small, malnourished infants carries a much higher likelihood of perforation rvith serious consecluences. Intestinal biopsy
{:y r:: I * s Se * r' * ;p,tS * l: ;s n t: * s i l; Cyclospora is a unicellular coccidian parasite recognized
1,979 to be a cause of diarrhea. It causes watery, cxplosive diarrhca that may continue lbr a month or more and may become chronic rvith severe weight loss in immunocomprornisecl individuals. Sources include contaminated u,ater and food, especiallv fragile items of fresh produce that cannot be u,ashed rigorously aftcr harvesting. Outbreaks have occurretl from unpasteurized apple cider and imported raspberries. Diagnosis is based on
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identification of oocysts in acid-fhst stained fbcal specimer-rs. Trimethoprim-sulfamethoxazole has proven an effective therapy in controlled trials.
Diarrhea in lnfants
IDI
also is knolvn as postenteritis enteropathv, protracted diarrhea ofinfancy, secondary disaccharidase delJ Ptdratrrcr in Revieir .,
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