AG A Te ch n ica l R e vie w o n th e E va lu a tio n a n d M a n a g e m e n t

o f C h ro n ic D ia rrh e a
Thisliteraturereviewandtherecommendationsthereinwerepreparedfor theAmericanGastroenterological AssociationClinical
PracticeandPracticeEconomicsCommittee. Thepaper wasapprovedbythecommitteeonSeptember 27, 1998.
C
hronic diarrheais acommon complaint of patients
presenting to family practitioners, internists, and
gastroenterologists. The differential diagnosis is com-
plex, andthevarietyof testsapplicabletothesepatients
can bebewildering. Accuratediagnosis may beelusive,
and treatment can be frustrating. The purpose of this
reviewistosummarizethemedical literaturepertinent to
the clinical evaluation and treatment of patients with
chronicdiarrheatoprovideasoundbasisfor dealingwith
thesepatients and to identify issues that could benefit
fromfurther research.
ThecomputerizedMEDLINEdatabasefor 19661997
was queried using the keywords chronic, diarrhea,
and diarrhea, diagnostic evaluation, and articles in
English wereselected for review. Pertinent papers that
appeared in peer-reviewed journals wereread and were
used. In this literature search, several points became
obvious: (1) properlydesignedepidemiological andout-
come studies are scarce; (2) there is a lack of large,
controlledstudiesof diagnostictechniquesandempirical
treatment; (3) most recommendationsfor evaluationand
treatment are based on expert opinion, not evidence-
based reasoning; and (4) experts vary in their opinions
(probably because of referral bias and the absence of
convincing data), and relatively little consensus about
evaluationandtreatment existsat present. Thissituation
isunlikelytochangeuntil moredefinitiveinformationis
providedbyappropriatestudies.
This technical reviewfirst focuses on problems with
thedefinition of diarrhea and chronic. Thelimited
information availableabout prevalence, final diagnoses,
and economic impact is then reviewed, and theclinical
utility of various diagnostic tests is analyzed. An ap-
proachtothecomplaint of chronicdiarrheaispresented,
andempirical therapyisreviewedbriefly. Finally, direc-
tionsfor futureresearchareoutlined.
Def i ni t i on of Chroni c Di arrhea
Diarrhea is defined in the dictionary as an
intestinal disorder characterized by an abnormal fre-
quency and liquidity of fecal evacuations.
1
Although
increasedfrequencyof stools(3/day) isconsideredpart
of thedefinitionof diarrhea,
13
patientsgenerallydonot
consider increased frequency of defecation aloneasdiar-
rhea.
4
Ontheother hand, increasedliquidityholdsupas
acriterionusedbypatients.
5
Althoughstool weight has
beencitedfrequentlyasascientificdefinitionof diarrhea,
diarrheashould not bedefined solely in terms of fecal
weight (e.g., above the upper limit of normal fecal
weight, 200 g/day). Some individuals have increased
fecal weight (sometimesashigh as300g/day) but have
normal stool consistencyanddonot complainof diarrhea.
Othershavenormal fecal weight andcomplainof diarrhea
becausetheir stoolsarelooseor watery.
5
A recent study has shed some light on objective
determinantsof decreasedfecal consistency.
5
Considering
a variety of potential factors, it was reported that the
presenceof water-insolublefecal solids(suchasthosethat
might be derived fromsome forms of dietary fiber or
bacterial cell walls)andtheir abilitytoholdor bindwater
intermsof thetotal amount of water present inthestool
correlatedbest withfecal consistencyasmeasuredobjec-
tively. If therewas too littlewater-holding capacity to
bindall of thewater present, stool consistencywasloose,
eventuallytothepoint of havingthepouringproperties
of water. Ontheother hand, whenfecal solidshadenough
water-holdingcapacityandtherewasonlyascant amount
of nonbound (free) water, stools remained thick or
formed. (This is similar to runny pancake batter that
thickens progressively as moreflour is added.) Thefact
that fecal consistency best relates to this ratio (i.e.,
water-holding capacity of insoluble solids/total water)
rather than theamount of water present per sefurther
supports the concept that stool weight should not be
consideredinthedefinitionof diarrhea.
Having defined diarrheaasadecreasein fecal consis-
tency, we must consider the duration of symptoms
necessarytodefinechronicdiarrhea. Unfortunately, there
has been and still is no consensus definition of chronic
diarrhea.
6
The optimal definition will depend on the
purposefor whichit isproposed, i.e., whether it isfor a
reviewsuchasthis, for aclinical study, or for aparticular
GASTROENTEROLOGY 1999;116:14641486
patient beingevaluatedinclinical practice. Whatever the
setting, the definition should include a period long
enoughtoallowmost casesof acutediarrheatoruntheir
courses. This is because the causes of acute diarrhea
(mostly self-limited infections) and chronic diarrhea
(mostlynoninfectiousetiologies) differ. Four weeksprob-
ably is the shortest duration of diarrhea that could be
considered chronic by this criterion, and 68 weeks
wouldprovideevenmoreof adistinction. Weuse4weeks
asour cutoff for clinical purposes.
D iffe re n tia tio n o f C h ro n ic D ia rrh e a F ro m
I rrita b le B o we l S yn d ro m e a n d F e ca l
I n co n tin e n ce
Theirritablebowel syndrome(IBS) is currently
defined by consensus as thecombination of abdominal
painandabnormal bowel habits(constipation, diarrhea,
or variable bowel movements) in the absence of other
defined illnesses.
7
For many years, painless chronic
diarrheawasincludedasavariationof IBS, but thisisno
longer tenable, giventheemphasisonabdominal painin
the current definition of IBS. Patients with painless
diarrheamay haveafunctional process (i.e., without a
knownorganiccause) but shouldnot becharacterizedas
havingIBS. Functional diarrhea shouldnot beconsid-
ered a final diagnosis; many of these patients have a
specific, definable problem that can be discovered by
appropriatetestingandcanbetreatedeffectively.
Fecal incontinence poses another problem.
8
Many
patients will not volunteer this symptom and instead
explainit tothephysicianasdiarrhea. Althoughmanyof
thesepatients haveloosestools, their major problemis
withthemechanismsof continenceandnot withintesti-
nal fluid and electrolyte absorption. Tests designed to
evaluatethesymptomof diarrheamaynot helppatients
with disordersof continence. All patientswith diarrhea
should be queried about the presence of fecal inconti-
nence; if incontinence is present frequently, especially
with low-volumestools, thesepatientsshould beevalu-
atedfor incontinenceandnot for diarrhea.
Preval ence of Chroni c Di arrhea and
It s Causes
The precise prevalence of chronic diarrhea is
unknown. AccordingtotheWorldHealthOrganization,
theprevalenceof chronicdiarrheainchildrenworldwide
rangesfrom3%to20%.
9
Reliableinternational datafor
adults are lacking. Surveys of Americans have yielded
varyingprevalencerates. For example, arecent surveyof
144randomlyselectedindividualsfromalargemetropoli-
tanareaindicatedthat 4%hadlooseor waterystoolsat
least 3 days aweek for 6 continuous months.
10
When
chronicdiarrheawaslessstringentlydefinedaspassageof
morethan threebowel movementsper day and/or loose
stoolsat least 25%of thetime, theprevalenceincreased
to 14%18%.
3,11
Many of thesepeoplehad abdominal
pain compatible with the IBS. When only patients
without abdominal painareconsidered, thenumber with
more than three bowel movements daily was 3%.
12
Diarrhea persisted 1220 months in 94% of these
individuals. Althoughpopulationdifferencesmayinpart
beresponsiblefor thewiderangeof reportedprevalence
rates, themajor factor isprobablydifferingdefinitionsof
chronicdiarrhea.
6
Basedonexcessivestool frequency(the
most widely used criterion), the prevalence of chronic
diarrheaintheUnitedStatesseemstobeapproximately
5%.
1012
Themaincausesof chronicdiarrheaseemtodependon
thesocioeconomic statusof thepopulation surveyed. In
developedcountries, themost frequent diagnosesmadein
patientswithchronicdiarrheaareIBS, idiopathicinflam-
matory bowel disease, malabsorption syndrome, chronic
infections, and idiopathic secretory diarrhea(which also
may be a chronic, but eventually self-limited, infec-
tion).
1318
Inlessdevelopedcountries, chronicbacterial,
mycobacterial, and parasitic infections are the most
commoncausesof chronicdiarrhea; functional disorders,
inflammatory bowel disease, and malabsorption (froma
variety of unspecified causes) are also common in this
setting.
1924
Withinagivenpopulationor country, theprevalence
of different causesof chronicdiarrheaisinfluencedbythe
level of subspecialization and the referral base of the
particular institutionreportingitsfindings. For example,
surreptitious laxativeabuseis common in tertiary care
referral centers with a focused interest in diarrheal
disorders but may be uncommon in primary care set-
tings.
13,25
Thefrequencyof variousdiagnosesinpatients
with undiagnosed or refractory diarrhea seen at our
institutionillustratesthissort of referral bias(Table1).
17
Economi c Impact of Chroni c
Di arrhea
Observation of patients with chronic diarrhea
suggests that chronic diarrheacan beadisabling prob-
lem. Many patients cannot maintain employment be-
causeof theneed for or threat of frequent trips to the
toilet. Intheabsenceof credibleincidenceor prevalence
data for diarrhea per se, it is difficult to estimate the
economic impact of disability dueto chronic diarrhea.
For example, the National Health Interview Survey,
19831987, reported aprevalenceof enteritis of just
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 6 5
under 1% of the population.
26
Six percent of these
individuals(0.06%of thepopulation) had somelimita-
tion of activity as aresult of this illness, amounting to
20,319,000restricteddaysper year, including3,114,000
worklossdays. At current medianincomes, theworkloss
alone accounts for an economic loss of more than
$350,000,000annually. Thecostsof medical care, disabil-
ity payments, and lost productivity are in addition to
this. It isnot clear fromavailabledatahowmanyof these
patientswithenteritis hadchronicdiarrheaasthemain
symptom, and it is unknown how many patients with
chronic diarrhea were not included in this diagnosis.
Thus it is impossible to calculate the societal cost of
chronicdiarrheaaccuratelywithcurrentlyavailableinfor-
mation.
Ef f ect of Chroni c Di arrhea on
Qual i t y of Li f e
Chronicdiarrheacanreduceapatientsqualityof
life. Thishasbeenbest demonstratedinpatientswiththe
humanimmunodeficiencyvirus(HIV)surveyedinNorth-
ern Californiaand in NewEngland.
27,28
Although diar-
rheacanbeamarker of moreprofoundimmunosuppres-
sion in thesepatients, it seemed to bean independent
predictor of quality of lifescores: patients with chronic
diarrheahadsignificantlyworsequalityof lifescoresthan
similar patientswithout diarrhea. Thisinformationisnot
availablefor other clinical situations.
Eval uat i on of Di agnost i c Test s
Some degree of diagnostic testing is usually
indicatedinpatientswithchronicdiarrhea. Thefollow-
ing sections discuss thespecifics of sometests applied
commonlyinpatientswithchronicdiarrhea.
M e d ica l H isto ry
Although the facets of an appropriate medical
history for patients with chronic diarrheaarenumerous
(see below), a few features separate certain general
disordersfromothers, specificallyfunctional fromorganic
causes. Indicators of a functional etiology are long
duration of symptoms (1 year), lack of significant
weight loss(5kg), absenceof nocturnal diarrhea, and
straining with defecation.
15,16
Theseindicators areonly
about 70%specificfor functional problems.
16
S p o t S to o l An a lysis
Randomlycollecteddiarrheal stool specimenscan
betested for blood, pus, fat, microbes, pH, electrolyte
andmineral concentrations, andlaxatives. Thesetestscan
providecluestothecauseof diarrhea.
O ccu lt b lo o d . Theutility of guaiac card testing
in the evaluation of chronic diarrhea has not been
publishedassuch. A studyfromour institutionshowed
that laxative-induced diarrhea, pancreatic maldigestion,
idiopathic secretory diarrhea, and microscopic colitis
wereassociated with fecal occult blood positivity rates
equal to thoseof normally formed stools.
29
In contrast,
approximately 50% of patients with celiac sprue and
70%of patientswithrefractoryspruehadguaiac-positive
stools.
29
Thesensitivityandspecificityof theguaiaccard
test for the detection of inflammatory or neoplastic
conditionscausingdiarrheahasnot beendetermined.
Wh ite b lo o d ce lls. Thestandardmethodof detect-
ing whiteblood cells(WBCs) in stool iswith Wrights
staining and microscopy.
30,31
The accuracy of the test
resultsdependsprimarily on theexperienceand skill of
theobserver. Bothfalse-positivesandfalse-negativescan
occur, and the significance of a result specifying few
WBCsseen isunknownandfrustrating.
A recently developed latex agglutination test for the
neutrophil product lactoferrin is highly sensitive and
specificfor thedetectionof neutrophilsinstool inacute
infectious diarrhea and in pseudomembranous colitis
causedbyClostridiumdifficile.
3234
Theusefulnessof this
test in the setting of chronic diarrhea has not been
reported.
S u d a n sta in fo r fa t. Dataontheutilityof Sudan
staining for qualitative assessment of the amount and
chemical structureof stool fat (triglyceridesvs. freefatty
acids) werepresentedinonestudypublishedintheearly
1960s.
35
Inthat report, fat loss(expressedasapercent of
intake) correlated with thenumber and sizeof Sudan-
Tabl e 1. Diagnostic Categories of 193 Patients With
Undiagnosedor Difficult toManageChronic
DiarrheaSeenat Baylor UniversityMedical Center,
Dallas, 19851990
Diagnostic category n %
Lowvolumesyndromes
a
41 21.2
Idiopathic secretorydiarrhea 39 20.2
After surgery
b
39 20.2
Microscopic/ collagenous colitis 29 15.0
Small bowel dysfunction
c
21 10.8
Exocrinepancreatic insufficiency 10 5.2
Inflammatorybowel disease 5 2.6
Radiationenteritis 5 2.6
Laxativeabuse 4 2.1
a
Includes IBS, hyperdefecationsyndromes, andfecal incontinence.
b
Includes postvagotomy, postgastrectomy, postcholecystectomy, and
postintestinal resectiondiarrhea.
c
Includes small bowel bacterial overgrowth, carbohydrate malabsorp-
tion, diabetes mellitus, motility disorders, Strongyloides infestation,
sprue, andspruelikeillnesses.
Reprintedwithpermission.
17
1 4 6 6 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
stainedfat dropletsviewedmicroscopically. Thetest was
86% specific for a fat output of 5% of intake and
87%100% sensitive for fat outputs of 6%15% of
intake.
35
However, theuseof percent of intakeastheunit
of fat excretion(asopposedtothecurrent standard, grams
excretedper day) andqualitativeexpressionof theresults
(asnormal, slight increase, anddefiniteincrease) haveled
to confusion in interpretation of the significance of a
positivequalitativefat test result. Furthermore, ahigh
level of observer skill and experience is critical to the
accuracy of the microscopic interpretation. In a more
recent study, thenumber of stainedfat dropletscounted
in a hematocytometer correlated well with fat output
measuredchemically.
36
However, thismethodwasevalu-
atedinonly41patientsandhasnot beenappliedwidely
elsewhere. Theoriginandtypesof fatsthat yieldpositive
resultsonSudanstaininghavebeenexploredinanother
publication.
37
An alternative, semiquantitativemeasure
of stool fat content, thesteatocrit, hasbeenusedmainly
in children and correlates well with quantitative fat
output asmeasuredusingthevandeKamer method.
3840
F e ca l cu ltu re s. Because bacterial infections are
rarelythecauseof chronicdiarrheainimmunocompetent
patients, routinefecal culturesusuallyarenot obtainedin
most individualswithchronicdiarrhea. However, at least
onefecal cultureshould beperformed at somepoint in
theevaluation of thesepatients.
41,42
Cultureson special
mediaand under specific environmental conditions are
requiredtolookfor Aeromonasor Pleisiomonasspecies.
4348
The epidemiological clues raising suspicion for the
presence of these organisms include consumption of
untreatedwell water andswimminginfreshwater ponds
andstreams.
44
In immunocompromised patients, but only rarely in
normal hosts, commoninfectiouscausesof acutediarrhea,
such as Campylobacter or Salmonella, can causepersistent
diarrhea.
49,50
Inthispopulation, bacterial culturesought
tobepart of theinitial diagnosticevaluation.
Infections with yeast and fungi, mainly Candida
albicans, havebeenreportedascausesof bothnosocomial
andcommunity-acquiredchronicdiarrhea, eveninimmu-
nocompetent individuals.
5154
Increasing use of broad-
spectrumantibioticswithgreater killingpower maybe
selecting for overgrowth of what had previously been
viewed as part of the normal flora. The yield of gram
stainsof stool andfungal culturesandtheappropriateness
of their useinpatientswithchronicdiarrheaof unknown
originhavenot beenstudied.
Protozoa and parasites are endemic in third world
countries but can also affect both immigrants to and
natives of developed countries, including the United
States. Poorlysensitivecytological andpathological tests
for detection of Giardia lamblia are being replaced by
moresensitiveandspecificmethodsof detection, suchas
fecal enzyme-linked immunosorbent assay (ELISA) for
Giardia-specific antigen.
55
Although the old-fashioned
stool examination for O and P remains popular, its
positive and negative predictive value in developed
countriesisundefined. Observer skill isessential tothe
success of this stool examination.
56
Detection of some
pathogens, such asStrongyloideslarva, may beof clinical
importance; however, cysts and ovaof other organisms,
includingEntamoebahistolytica, maybeinnocent colonists
rather thanpathogens, especiallyininhabitantsof third
world countries.
57
Special techniques are required to
detect cryptosporidia and microsporidia in stool; these
organisms may causediarrheain immunocompetent as
well asimmunocompromisedpeople. Chronicviral infec-
tions (a diagnostic consideration practically limited to
immunocompromised hosts) usually arediagnosed from
gastrointestinal mucosal biopsy specimens rather than
stool samples.
pH , e le ctro lyte s an d m in e rals, an d laxative s. The
utilityof thesemeasurementsonaspot stool specimenis
thesameaswhen they aremeasured in aquantitatively
collectedspecimen, asdiscussedbelow.
Quant i t at i ve St ool Col l ect i on and
Anal ysi s
A 48- or 72-hour quantitativestool collection is
useful inthework-upof chronicdiarrhea. Althoughthis
test is not necessary in every case, it can behelpful in
characterizing the volume of diarrhea and segregating
likelydiagnosticpossibilitiesfromlesslikelyones(e.g.,
byfindingsignificant steatorrhea). However, thepoten-
tial benefits of obtaining thesemeasurements (e.g., less
costly directed work-up or fewer patient complications
frominvasiveprocedures) havenot beenestablished. The
necessarydurationof thecollectionhasnot beendefined
scientificallyfor clinical purposes. Ingeneral, thehigher
thedailystool weight is, themoreaccurateandrepresen-
tativeshorter collectionperiodscanbe. Practical consid-
erationsmandatea48-hour collectionfor most inpatients
andoutpatients. Inpatientsinwhom48-hour collection
yieldsasmall or unrepresentativesample, thecollection
canbeextended.
G e n e ra l p rin cip le s. Full analysisof thecollection
includesmeasurement of weight, fat content, osmolality,
electrolyteconcentrations, magnesiumconcentrationand
output, pH, occult blood, and when appropriate, fecal
chymotrypsin or elastase activity (for assessment of
pancreatic function) and screening for laxatives. If these
analyses cannot be performed locally, many clinical
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 6 7
laboratoriesandreferral hospital laboratoriescananalyze
arepresentativealiquot of stool (approximately 200 g)
takenfromahomogenizedcollectionafter it isweighed.
(Thealiquot shouldbefrozenimmediately; if mailingis
necessary, it shouldbemailedinacontainer packedwith
dryice, alongwitharecordof thetotal weight of the48-
or 72-hour collection.)
Quantitative stool collection can be done easily and
successfully at home or in the hospital. Some simple
equipment can facilitatecollection, including adispos-
able collection unit that fits onto the commode and
allowsseparation of stool and urine, several preweighed
containers for the collected stool (e.g.,plastic or metal
containers with airtight lids that hold at least 1 or 2 L
each), andareceptacletokeepthesecollectioncontainers
cold during the collection period, such as a small,
portable refrigerator (usually used for inpatients) or a
picnic cooler containing refreezable blue ice packs
(ideal for outpatients).
Several days beforeand during thecollection period,
thepatient shouldeat aregular diet of moderatelyhigh
fat content. It maybeuseful toprescribeafixeddiet for
somepatientstoensurethat adequateamountsof fat and
caloriesareconsumed. Weencouragepatientstoconsume
80100 g of fat during the collection, but fractional
absorption can be calculated for any intake. During
collection, the patient should keep a record of bowel
activity and a diary of food and liquid intake(so that
calorie, fat, carbohydrate, and fiber intakecan beesti-
matedfromdietarytables). Duringthecollectionperiod,
nodiagnostictestsshouldbedonethat woulddisturbthe
normal eatingpattern, aggravatediarrhea(e.g., lactose
or D-xyloseabsorptiontestsor testsusingenteral iodin-
ated contrast media), diminish diarrhea (by requiring
fastingor useof opiates), addforeignmaterial tothegut
(e.g., bariumradiography studies), or risk an episodeof
incontinence. All but essential medications should be
avoided, and any antidiarrheal medication begun before
thecollectionperiodshouldbeheld.
Stool output may vary considerably fromday to day
and week to week. When evaluating the results of a
quantitativestool analysis, thephysician needstoknow
whether thesubmittedstool wascollectedduringatime
that thepatient washavingwhat heor sheconsideredto
bediarrhea. It isadvantageousfor thephysiciantolookat
thecollectedspecimenandassessstool consistencyvisu-
allybecausethedefinitionof diarrheadependsonthefact
that stoolsareabnormallylooseor liquid.
F e ca l we ig h t. Knowledge of stool weight may
helptoclarifythenatureof thepatientsproblemandto
localize the region of the intestine most likely to be
responsiblefor diarrhea(althoughthereliabilityof thisis
untested). Insomeinstances, knowledgeof stool weight
is of direct help in diagnosis and management. For
example, stool weightsgreater than500g/dayarerarely
if ever seeninpatientswithIBS,
58,59
andstool weightsof
less than 1000 g/day are evidence against pancreatic
cholerasyndrome. Also, veryhighstool weightsalert the
physiciantothepossibleneedfor vigorousfluidreplace-
ment; patients with stool weights greater than 2000
g/day usually require supplemental intravenous fluids.
Low stool weight in a patient complaining of severe
diarrhea suggeststhat incontinenceor painmaybethe
dominant problem.
Onrareoccasions(e.g., whenfecal volumesareextraor-
dinarilyhighor thereappearstobebothamalabsorptive
andasecretorycomponent tothediarrhea), it isuseful to
determinethedegreeto which diarrheapersists during
fasting. Continuationof diarrheaduringa48-hour fast is
one criterion for classification of the diarrhea as a
secretory (nonosmotic) process.
60
(Fecal weight may
decrease some with fasting, even in secretory diarrhea,
becausefluid input to theintestinedecreases; however,
continued diarrhea on the second day of fasting is an
indicator of asecretoryprocess.) Alternatively, complete
cessation of diarrhea during fasting is strong evidence
that the mechanism of diarrhea involves something
ingested (which could beanonabsorbablesubstanceor
nutrient causing osmotic diarrhea, or unabsorbed fatty
acids or laxatives causing secretory diarrhea). The re-
sponse to fasting is more helpful for determination of
pathophysiology, therebylimitingthespectrumof poten-
tial diagnoses, rather thanfor makingaspecificdiagno-
sis.
61,62
E le ctro lyte s a n d ca lcu la tio n o f a n o sm o tic g a p .
Fecal electrolyte concentrations are measured in stool
water after homogenization of the entire specimen (by
manual stirringor inamechanical blender) andcentrifu-
gation of an aliquot to obtain supernatant for analysis.
Placement of dialysisbagsinthestool isanother reported
but lesscommonlyusedmethodof obtainingstool water
for analysis.
63
Theosmoticgapof fecal fluidcanbeused
toestimatethecontributionof electrolytesandnonelec-
trolytestoretentionof water intheintestinal lumen. In
secretorydiarrhea, unabsorbedelectrolytesretainwater in
the lumen; in osmotic diarrhea, nonelectrolytes cause
water retention. The osmotic gap is calculated from
electrolyteconcentrationsinstool water bythefollowing
formula: 290 2([Na

] [K

]). The sum of the

sodiumandpotassiumconcentrationsismultipliedbya
factor of 2toaccount for associatedanions. Theosmolal-
ityof stool withinthedistal intestine(estimatedas290
mOsm/kgbecauseit equilibrateswithplasmaosmolality)
should be used for this calculation rather than the
1 4 6 8 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
osmolalitymeasuredinfecal fluid, becausemeasuredfecal
osmolalitybeginstoincreasein thecollection container
almost immediatelywhencarbohydratesareconvertedby
bacterial fermentationtoosmoticallyactiveorganicacids.
The advantages of using 290 mOsm/kg instead of
measured fecal osmolality for calculation of the fecal
osmoticgaphavebeensubstantiatedintwostudies.
64,65
Theosmoticgapshouldbelarge(125mOsm/kg) in
pureosmoticdiarrhea, inwhichnonelectrolytesaccount
for most of theosmolalityof stool water, andsmall (50
mOsm/kg) in puresecretory diarrhea, in which electro-
lytes account for most of stool osmolality.
64
In mixed
osmotic and secretory processes and in cases of modest
carbohydratemalabsorption(inwhichmost of thecarbo-
hydrateloadisconvertedtoorganicanionsthat obligate
thefecal excretionof cationsincludingNa

andK

), the
osmoticgapmayliebetween50and125.
64
M e a su re d o sm o la lity. Although measured fecal
fluid osmolality should not be used to calculate the
osmoticgap, measurement of fecal fluidosmolalitymay
be useful in patients with unexplained diarrhea. Low
osmolalities(290mOsm/kg) indicatecontaminationof
stool with water or diluteurine
66
or thepresenceof a
gastrocolic fistulaand ingestion of hypotonic fluid. As
mentioned previously, osmolalities of 290 mOsm/kg
are common because of bacterial metabolism of fecal
carbohydrateduring storageof thestool sample(up to
600 mOsm/kg). Even higher valuesfor fecal osmolality
canbeobservedwithingestionof largeamountsof poorly
absorbable carbohydrate or dietary fiber, with fecal
contamination by concentrated urine, or with agastro-
colicfistulaandingestionof hypertonicfluids.
F e ca l p H . A low fecal pH is characteristic of
diarrhea caused solely by carbohydrate malabsorption.
Theresultsof measurement of fecal pH inexperimentally
induced diarrhea showed that a fecal pH of 5.3
indicates that carbohydratemalabsorption (such as that
associatedwithlactuloseor sorbitol ingestion) isamajor
causeof diarrhea, whereas apH of 5.6 argues against
carbohydrate malabsorption as the only cause of diar-
rhea.
64
In generalized malabsorption syndromethat in-
volvesfecal lossof aminoacidsandfattyacidsinaddition
to carbohydrate, the fecal pH usually is higher (e.g.,
6.07.5).
67
F e ca l fa t co n ce n tra tio n a n d o u tp u t. Theconcen-
tration of fat per 100 g of stool can bequantitated by
either titrationor gravimetricmethods,
6872
andthedaily
excretionrateisobtainedbymultiplyingthisconcentra-
tionbytheaveragedailyweight of the2- or 3- daystool
specimen. Inmost clinical laboratories, theupper limit of
normal for daily fecal fat output measured in normal
subjects(without diarrhea) ingestingnormal amountsof
dietary fat is approximately 7 g/day (9% of dietary fat
intake). By definition, values greater than this are
abnormal and signify thepresenceof steatorrhea. How-
ever, inastudyof normal subjectswithinduceddiarrhea
(stool weights up to 1400 g/day), 35% had fecal fat
excretionmeasuredabovetheupper limit of normal, with
valuesashighas13.6g/day.
73
Thus, evenwhenmecha-
nisms of digesting and absorbing dietary fat areintact,
diarrhea itself causes steatorrhea (secondary steator-
rhea). Therefore, inpatientswithdiarrhea, anabnormal
fecal fat valuebetween7and14g/dayhaslowspecificity
for thediagnosis of primary defects of fat digestion or
absorption. On theother hand, abnormal values of 14
g/dayor higher aremorespecificfor diseasesthat impair
fat digestion or absorption (i.e., diseasesof theexocrine
pancreas, thesmall intestinal mucosa, or theenterohe-
paticcirculationof bilesalts).
Dietaryfat intakeduringthestool collectionshouldbe
estimatedfromadiet diary. Most patientswithdiarrhea,
especially patients with malabsorption, curb their food
intake(particularlyof fattyfoods) inanattempt tolessen
their diarrhea. Nauseaandanorexiamayalsolimit dietary
fat intake. If this is done during quantitative stool
collection, patients with malabsorptive disorders may
have fecal fat outputs lower than expected for their
syndrome. Stool fat excretionnormallyshouldbe9%of
dietaryintake.
Althoughthereportedfat concentrationinstool (i.e.,
fat per 100 g of stool) frequently is ignored, fecal fat
concentrationmayprovideacluetothecauseof steator-
rhea. Inonestudyafecal fat concentrationof 9.5g/100
gof stool wasmorelikelytobeseeninsmall intestinal
malabsorptivesyndromesbecauseof thediluting effects
of coexisting fluid malabsorption, whereas fecal fat
concentrations of 9.5 g/100 g of stool were seen in
pancreaticandbiliarysteatorrhea, inwhichfluidabsorp-
tioninthesmall bowel isintact.
74
Althoughinthisstudy
the test was 100% sensitive, a second study found a
sensitivityof only42%.
75
However, specificitywashigh
inbothstudies(80%92%), meaningthat, whenpresent,
ahighfecal fat concentrationshouldsuggest thepresence
of pancreaticor biliarysteatorrhea.
Te sts fo r fe ca l ca rb o h yd ra te . Althoughtestsfor
carbohydratecontent arenot doneroutinelyoncollected
stool, qualitativetests for carbohydrates can beused to
identifymalabsorbedcarbohydrates. However, thesetests,
originallydesignedfor measuringurinarycarbohydrates,
havenot been standardized for stool analysis. Based on
thereagentsintheseproducts, thefollowingconclusions
arelikely: dipsticksbasedonglucoseoxidaseshouldgive
apositivereaction with glucoseand should benegative
with all other sugars; Clinitest tablets (Ames Division,
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 6 9
Miles Laboratories, Elkhart, IN) should giveapositive
reaction with glucose, galactose, fructose, maltose, and
lactose (reducing sugars) but a negative result with
sucrose, lactulose, sorbitol, and mannitol (nonreducing
sugars or sugar alcohols). Anthrone reagent, used as a
researchtool toquantitatefecal carbohydrate,
76
issensi-
tivetothepresenceof starches, oligosaccharides, disaccha-
rides, and all hexoses but does not detect sorbitol and
mannitol (sugar alcohols).
An a lysis fo r la xa tive s. Diagnosis of factitious
diarrhearequiresahighindexof suspicion. Analysisfor
laxatives should be done early in the evaluation of
diarrhea of unknown etiology.
23,7779
Because patients
mayingest laxativesintermittently, negativestudiesmay
havetoberepeated.
77,80
Thesimplest test for alaxativeis
alkalinizationof 3mL of stool supernatant or urinewith
onedrop of concentrated (1N) sodiumhydroxide. This
will result in a pink or red color with a maximal
spectrophotometricabsorptionof 550555nmif phenol-
phthalein is present.
81
(Phenolphthalein has been with-
drawn fromthemarket in theUnited States becauseof
fearsof carcinogenicitybut maybeavailableelsewhere.)
Stool water canbeanalyzedspecificallyfor phenolphtha-
lein, emetine (one component of ipecac syrup),
82
and
bisacodyl and its metabolites,
83
using chromatographic
or chemical tests. Urinecan beanalyzed for anthraqui-
nonederivatives.
84,85
Insearchingfor surreptitiouslaxativeingestion, stool
water should be analyzed for osmolality and electro-
lytes.
86
If findings suggest secretory diarrhea (osmotic
gap 50), the patient may have ingested a laxative
capableof causingsecretorydiarrhea. Diarrheacausedby
sodium sulfate or sodium phosphate ingestion also
appearstobeasecretorydiarrheabyelectrolyteanalysis,
even though pathophysiologically it is an osmotic diar-
rhea. This occurs becausethenegativecharges of unab-
sorbedsulfateor phosphateobligatesodium, potassium,
and other cationsremain in thecolonic lumen.
64,87
The
fecal concentration and daily output of sulfate and
phosphatecanbemeasuredbychemical testing, but the
upper limitsof normal havenot beenestablished. A high
fecal sodiumconcentrationinthepresenceof alowfecal
chlorideconcentration shouldalsoraisethesuspicion of
ingestionof sodiumsulfateor sodiumphosphate.
64
If stool electrolyteanalysis suggests osmotic diarrhea
(osmotic gap 125 mOsm/kg), magnesium (Mg
2
)
laxatives may have been ingested. A soluble fecal Mg
concentration greater than 45 mmol/L (90 mEq/L) or a
daily fecal Mg output much above 15 mmol/day (30
mEq/day) stronglysuggestsMg-induceddiarrhea.
88
Fac-
titiousdiarrheamaybecausedbydeliberatecontamina-
tion of a stool collection with water urine. If fecal
osmolality is significantly less than 290 mOsm/kg (the
osmolalityof plasma), water or hypotonicurinehasbeen
addedtothestool.
66
If theosmolalityisfar abovethat of
plasma, hypertonic urinemay havebeen added tostool
(although this finding also may be caused by the
production of fermentation products in vitro). Urinary
contamination can be confirmed by a finding of high
monovalent cationconcentration(e.g., [Na

] [K

]
165, physiologicallyimpossibleinstool water)andahigh
concentrationof ureaor creatinineinstool water.
Becausemanyinstitutionslack analytical methodsfor
all available laxatives, searching the patients hospital
room or home for hidden laxatives has been used to
establishthediagnosisof factitiousdiarrhea. Discoveryof
caches of laxatives can also be helpful in convincing
relativesthat thediarrheaiscausedbylaxativeingestion.
Inoneseries, aroomsearchhadahigher diagnosticyield
for factitious diarrhea than any other test.
89
However,
some physicians think that it is unethical invasion of
privacytosearchapatientsbelongingsfor laxativesand
diureticswithout permission. Othersbelievethat asearch
should be viewed as a diagnostic study, requiring in-
formed consent and including a discussion with the
patient of the procedure, its risks and benefits, and
alternatives.
90
On the other hand, failure to discover
laxativeabusemay lead to needless hazardous tests and
treatment, such asinsertion of central venouscatheters,
administrationof total parenteral nutrition, anddiagnos-
ticand/ortherapeutic operations, suchaspartial pancre-
atectomy and total colectomy. Even more importantly,
laxativeabusemaybefatal inchildrenwhosecaregivers
are poisoning them with laxatives.
87,91
Despite the
potential of protecting the patient from self-induced
harm, the legality of searching a patients belongings
without permissionisquestionable, andsuchsearchesare
discouragedbymost attorneys. Becauselaxativeassaysare
readilyavailablefromreferencelaboratories, roomsearches
shouldbedoneonlyunder exceptional circumstances.
Te sts fo r p ro te in -lo sin g e n te ro p a th y. A diagno-
sis of protein-losing enteropathy should be considered
whenapatient hashypoalbuminemiabut doesnot have
nephrotic syndrome or hepatic dysfunction. Confirma-
tionof entericproteinlosscancomefrommeasurement of
thefecal clearanceof
1
-antitrypsin.
92
Clearanceof this
protein fromplasmaviatheintestinal tract is based on
the same concepts as renal inulin clearance and is
calculatedinsimilar fashion. Radioimmunoassayisused
to measure
1
-antitrypsin concentrations in stool and
plasma; total fecal output is calculated fromconcentra-
tionandvolumeandisdividedbyplasmaconcentration.
Measurement of the concentration of
1
-antitrypsin in
randomly passed stools has been tried as a simpler
1 4 7 0 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
methodtomeasureintestinal proteinlossinchildrenbut
has had only moderate success.
93
Fecal excretion of
radioiodinatedalbuminandimmunoglobulinGadminis-
teredparenterallyhasalsobeenreportedasamethodof
measuring enteric protein loss but is not available
routinely.
94,95
B lo o d a n d U rin e Te sts
An a lysis o f u rin e . Urinecollectionsmaybehelp-
ful for laxative identification and for measurement of
excretion of 5-hydroxyindole acetic acid (for carcinoid
syndrome), vanillylmandelicacid(VMA; forpheochromo-
cytoma, metanephrine(for pheochromocytoma), andhis-
tamine(for mast cell diseaseand foregut carcinoids). If
volumedepletionor hypokalemiaarepresent, analysisof
urineelectrolytescandeterminewhether renal conserva-
tion of sodium and potassium is appropriate. If the
urinaryconcentrationoroutput of sodiumorpotassiumis
inappropriately high, surreptitious diuretic usemay be
present andmaysuggest coexistinglaxativeabuse. Also,
measurement of urineelectrolytes and aldosteronemay
distinguish hypervolemiafromvolumedepletion in the
settingof hypernatremiacausedbyingestionof sodium-
containinglaxatives.
88
Va so a ctive in te stin a l p o lyp e p tid e a n d o th e r p e p -
tid e h o rm o n e s. Pancreatic cholera syndrome is a rare
cause of secretory diarrhea attributable to secretion of
vasoactiveintestinal polypeptide(VIP) by aneuroendo-
crine tumor. It should be suspected if diarrhea of
unknownoriginhaslastedlonger than4weeks, hasthe
clinical features of secretory diarrhea, has a volume
greater than1L/day, isassociatedwithhypokalemia, and
causes clinically significant volume depletion and if
surreptitious laxative and diuretic abuse and organic
diseaseof thegastrointestinal tract havebeenexcluded. It
isonlyinthisraresubgroupof patientsthat serumassay
for VIP islikelytobeuseful. Measurement of afewother
specificpeptidescanbehelpful inthediagnosisof other
neuroendocrine tumors. These include measurement of
calcitoninfor thediagnosisof medullarycarcinomaof the
thyroid, gastrin for suspected ZollingerEllison syn-
drome, and glucagon for therarepatient with agluca-
gonoma.
17
Measurement of largepanels of enteric pep-
tidesnot specificfor particular tumor syndromes, suchas
motilin, neurotensin, pancreatic polypeptide, substance
P, and gastrin-releasing peptide, should not bedonein
patients with chronic diarrhea because of their poor
specificityandextremelylowpositivepredictivevalue,
17
whichisattributabletotherarityof thesetumorsandthe
highfrequencyof false-positiveassays.
S e ro lo g ica l te sts. Serological teststhat occasion-
ally may provideuseful diagnostic information include
tests for antinuclear antibodies
96
; antigliadin immuno-
globulin (Ig) A and IgG antibodiesand antiendomysial
IgAantibodies
97103
; perinuclear antineutrophil cytoplas-
micantibodies
104107
; HLA typing
108110
; quantitationof
serumimmunoglobulin concentrations
111
; and antibod-
iestoHIV andEntamoebahistolytica(Table2).
Serological testingfor celiacsprueisof special interest,
not onlyfor diagnosisbut alsofor evaluationof patients
after treatment. Antigliadin IgA antibodies are more
specific, but lesssensitivefor adiagnosisof celiacsprue
(specificity, 67%100%; sensitivity, 69%100%) than
the IgG fraction (specificity, 47%70%; sensitivity,
89%100%). IgA antigliadin antibody also is more
predictiveof recent gliadin ingestion becauseafter 13
monthsof agluten-freediet, serumlevelsbegindecreas-
ing, and by 612 months they usually disappear if the
patientsdiet hasbeen completely gluten-free. TheIgG
serumfraction, on the other hand lingers longer than
IgA, andalthoughsomereductioncanbeseenover time,
Tabl e 2. Serological Tests That MayBeUseful inPatients
WithChronic Diarrhea
Test Disorders Application
Antinuclear antibody Vasculitis, sclero-
derma, celiac
sprue, microscopic
colitis, hypothy-
roidism, autoim-
muneenteropathy
Diagnosis
Antigliadin, antiendo-
mysial antibodies
Celiac sprue Diagnosis; follow-up
of conditionand
compliancewith
treatment
Perinuclear antineu-
trophil cytoplasmic
antibody
Ulcerativecolitis Diagnosis; distin-
guishingfrom
Crohns colitis
Quantitativeimmuno-
globulins
SelectiveIgAdefi-
ciency, common
variableimmuno-
deficiency
Diagnosis; assess-
ment of response
toIginfusions
HLA-DR, DQtyping Celiac sprue, refrac-
toryor unclassified
sprue, possibly
Crohns disease
andulcerative
colitis
Confirmationof a
diagnosis of celiac
sprue(byfinding
DR3 or DQ2) when
necessary;
assessment of
refractoriness ina
patient withasprue-
likeillness; inthe
futurepossiblyfor
thediagnosis
and/ or distinction
of Crohns and
ulcerativecolitis
Erythrocytesedimen-
tationrate, C-reac-
tiveprotein
Inflammatorybowel
disease
Diagnosis; response
totherapy; disease
activity
Antibodytiters toE.
histolytica
Amebiasis of the
colonand/ or liver
Diagnosis
Antibodies toHIV AIDS Diagnosis
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 7 1
IgG antigliadin antibodies may never disappear com-
pletely.
Antiendomysial antibodiesarethemost specificof the
serological tests for celiac sprue, with a specificity in
villousatrophic diseaseof nearly 100%. However, their
sensitivityhasrangedfromaslowas74%upto100%.
Thereisinadequateinformationregardingthesensitivity
of antiendomysial antibodies in less severe forms of
gluten sensitivity, but it may well belower. Until now,
theonly test to detect endomysial antibodies has been
indirect immunofluorescence in monkey esophagus or
human umbilical cord tissue substrates. As with all
immunofluorescent tests, correct interpretationof results
is highly dependent on the skill and experience of a
technician interpreting the fluorescence pattern in tis-
sues, andquantitationof theamount of antibodypresent
relies on repeat examinations after serial dilutions of
serum. An ELISA test that can detect and quantitate
serumendomysial antibody probably will be available
soonfor clinical use.
E n d o sco p ic E xa m in a tio n a n d
M u co sa l B io p sy
S ig m o id o sco p y a n d co lo n o sco p y. Examination
of the mucosa of the colon and rectum and mucosal
biopsy may beuseful in patientswith chronic diarrhea,
but it is unclear whether the initial procedure should
involvea60-cmflexiblesigmoidoscopyor afull colonos-
copy. Theadvantagesof theformer includeitsease(i.e.,
simplepreparation, noneed for sedation, shorter proce-
dure, andgreater chancefor successful completion), lower
risk of perforation, and lower cost. Patient acceptance
may bebetter or worsethan with colonoscopy (because
patients areusually sedated for colonoscopy). Themain
concernwithsigmoidoscopyisthat thecausativedisease
may bepresent only in theproximal colon or terminal
ileum and will be missed by a limited examination.
Althoughthiscanoccur inCrohnsdiseaseandother rare
idiopathic inflammatory conditions,
112
thepathological
process occurs diffusely throughout the colon in most
diseases that can bediagnosed by lower endoscopy. For
example, microscopicandcollagenouscolitisareusually
diffuseprocesses, but inflammatorychangesorsubepithe-
lial collagen band thickening may occur only in the
proximal colon in approximately 10%of patients.
113,114
Thus relatively few cases remain undiagnosed with
limited examination. Therefore, in light of the advan-
tages of flexiblesigmoidoscopy over colonoscopy listed
above, sigmoidoscopy can berecommended as thebest
initial test. Duringsigmoidoscopy, randombiopsyspeci-
mensshouldbeobtainedfromthedescendingcolon, the
sigmoid colon, and therectum(e.g., four biopsy speci-
mens taken every 1020 cm). When results of other
diagnostic tests raise a strong suspicion of a colonic
process(e.g., whenleukocytesor lactoferrinarepresent in
stool),whenthepresenceof inflammatorybowel diseaseis
suggestedbyspecificsymptomsor signs, or whenbiopsy
specimens fromthedistal colon areequivocal, colonos-
copymayprovideadditional helpful information. When
thereissignificant weight lossor grossor occult bleeding
to suggest malignancy, or when an abnormality of the
terminal ileumor proximal colon has been seen on an
imaging study or radiogram, it is appropriateto begin
endoscopic evaluation of thecolon with afull colonos-
copy. However, no prospective study has assessed the
utility and costsof limited vs. completeexamination of
thecolon in patientswith chronic diarrhea, although it
seemsthat completecolonoscopywouldbemoreexpen-
siveandrarelyleadstoanadditional diagnosis.
115
Chronicdisordersthat canbediagnosedbyinspection
of thecolonicmucosaincludemelanosiscoli, ulceration,
polyps, tumors, Crohns disease, ulcerative colitis, and
amebiasis.
116118
Diseases in which themucosaappears
normal endoscopicallybut that canbediagnosedhistologi-
callyincludemicroscopiccolitis(lymphocyticandcollag-
enous colitis), amyloidosis, Whipples disease, granu-
lomatous infections, and schistosomiasis in its chronic
form.
U p p e r tra ct e n d o sco p y. Upper endoscopy has
becomethestandardmethodfor obtainingbiopsyspeci-
mens from the upper small intestine.
119,120
If a small
intestinal malabsorptivedisorder is strongly suspected,
the procedure is probably best performed with an
endoscopethat allowsspecimenstobeobtainedfromthe
distal duodenumand/orproximal jejunumaswell asfrom
the proximal duodenum, although duodenal biopsies
may be adequate to discover most diffuse mucosal
diseases. An aspirateof small intestinal contentscan be
sent for quantitative aerobic and anaerobic bacterial
culture (using techniques used for quantitative urine
culture) if bacterial overgrowth is suspected and for
microscopicexaminationfor parasites. Diseasesthat may
bediagnosedbysmall intestinal biopsyincludeCrohns
disease, giardiasis, celiac sprue, intestinal lymphoma
withorwithout villousatrophy, eosinophilicgastroenteri-
tis, hypogammaglobulinemic sprue (with or without
nodular lymphoid hyperplasia), Whipplesdisease, lym-
phangiectasia, abetalipoproteinemia, amyloidosis, masto-
cytosis, andvariousmycobacterial, fungal, protozoal, and
parasiticinfections.
121123
Thepresenceof steatorrheaor
fecal occult bloodincreasesthelikelihoodof makingone
of thesediagnosesbyupper endoscopy.
1 4 7 2 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
R a d io g ra p h y
B a riu m ra d io g ra p h y. Therehavebeennoformal
studies of the utility of radiography in the diagnostic
evaluationof chronicdiarrhea. However, becausemost of
thesmall intestine(includingmost of theterminal ileum)
cannot be approached with standard endoscopes, ana-
tomicchangesarebest assessedwithbariumradiography.
Therearesituations in which apreviously unsuspected
diagnosisismadebysmall intestinal radiography(suchas
Crohnsdiseaseor jejunal diverticulosis). In other situa-
tions, abnormal findingswill leadtofurtherinvestigation
and, ultimately, adiagnosis. For example, amalabsorp-
tionpattern consistingof excessluminal fluid, dilation,
andanirregular mucosal surfacemayleadtoadiagnosis
of celiac sprue, Whipples disease, or intestinal lym-
phoma, althoughthismaybelesscommonwithmodern
bariumpreparations than in thepast.
124
Other diseases
that might bediagnosedwithsmall intestinal radiogra-
phyarecarcinoidtumorsandscleroderma.
Althoughit hasnot beentestedspecificallyinpatients
withchronicdiarrhea, thediagnosticyieldof small bowel
radiographyisabout thesamewhether bariumisadmin-
istered orally (small bowel follow-through examina-
tion) or byanenteroclysistube, providedthat thesmall
bowel follow-through study is performed by a dedi-
cated radiologist whopersonallywatchesthecolumnof
bariumandusesfluoroscopyintermittently(rather thana
technologist whoperformsoverheadradiographsat some
set timeintervals).
125,126
Thus, for thestudy of patients
with chronic diarrhea, enteroclysis probably has no
special role.
Radiographicstudiesof thestomachandcolonmaybe
complementary to endoscopy and colonoscopy because
barium-contrast radiogramscanbetter detect fistulasand
strictures. Radiography of thegastrointestinal tract also
helpstodelineateanatomyafter previoussurgical resec-
tionor bypass.
M e se n te ric a n g io g ra p h y. Small intestinal isch-
emia is a rare cause of chronic diarrhea.
127,128
In the
appropriateclinical setting, mesentericorceliacangiogra-
phymayshowevidenceof intestinal ischemiacausedby
atherosclerosis or vasculitis. The utility of magnetic
resonance imaging or spiral computed tomographic
angiographyinthissettingisnot clear.
C o m p u te d to m o g ra p h y. Computed tomography
isperformedinpatientswithchronicdiarrheatoexamine
for pancreaticcancer or evidenceof chronicpancreatitisin
the presence of malabsorption or when the results of
pancreatic function tests are abnormal. Inflammatory
bowel disease, chronic infections such as tuberculosis,
intestinal lymphoma, carcinoid syndrome, and other
neuroendocrinetumorsareadditional diagnosesthat can
berevealedbycomputedtomography. Inthecaseof the
tumors mentioned last, rapid computed tomography
scanning with thin (5 mmor less) sectionsthrough the
pancreas following a bolus of intravenous contrast is
recommended, although thedegreetowhich sensitivity
isincreasedover standardcomputedtomographicmeth-
odsisunknown.
P h ysio lo g ica l Te sts
M u co sa l a b so rp tio n . Testsof monosaccharideab-
sorption havebeen used classically to distinguish small
intestinal mucosal absorptive defects from pancreatic
digestivedefectsinthesettingof malabsorption. Inthe
1950s, theoral glucosetolerancetest wasreplacedbythe
D-xyloseabsorptiontest becauseof better reliabilityand
the lack of interference from endogenous serum glu-
cose.
129,130
Subsequently, an abnormal D-xyloseabsorp-
tiontest result becamesynonymouswithadiseasedsmall
intestine(barringconfoundingrenal dysfunctionor urine
collection problems) and was used to determine who
would be served best by capsule biopsies of the small
bowel. Today, with the widespread use of endoscopic
biopsies, the role of this test has become less clear,
althoughit still yieldsinformationabout small intestinal
absorptivefunction. Somecliniciansstill usethistest for
screeningor for followinguptheresponsetotreatment,
but the utility of this approach has not been assessed
formally.
Most verification studies of theD-xylosetest involve
patientswithceliacsprueor inflammatorybowel disease
of thesmall bowel.
129,130
Urinary excretion of less than
5ginthe5hoursfollowingingestionof 25gof D-xylose
is considered abnormal. A plasmaconcentration of less
than 1.3 mmol/L per 1.73 m
2
body surface area (20
mg/dL for anaverageadult) 1hour after a25-goral dose
isconsideredabnormal.
131
Te sts o f ile a l a b so rp tive fu n ctio n . Theterminal
ileumhas evolved threespecific and uniqueabsorptive
functions: absorption of vitamin B
12
, absorption of
sodiumchlorideagainst steepelectrochemical gradients,
and absorption of bile acids. Disruption of any one of
these, particularly of all three, can be seen in patients
with diarrhea. Therefore, tests have been developed to
assessthesespecializedileal absorptivefunctions.
Thetime-honoredtest of vitaminB
12
absorptionisthe
Schillingtest.
132
Inpatientsbeingevaluatedfor chronic
diarrhea(asopposedtothosebeingevaluatedfor vitamin
B
12
deficiency or macrocytic anemia), radiolabeled vita-
min B
12
is given with intrinsic factor (the so-called
SchillingII test). Thepositiveandnegativepredictive
valuesof thetest for ileal dysfunctioninalargegroupof
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 7 3
patientswithchronicdiarrheaof unknownoriginhasnot
been determined. With the widespread availability of
colonoscopy, which can visualize the terminal ileum,
sophisticatedradiographicimagingtechniques, andstan-
dard bariumradiography, theSchilling test is nowless
important intheinvestigationof chronicdiarrheathanin
thepast.
Theonlymethoddevelopedtostudyfluidandelectro-
lyte absorption in the ileum is intestinal perfusion.
Perfusion of asegment of ileumcan becarried out but
requirespainstakingeffort bythepatient andinvestiga-
tor toplacethetubeinthedistal small bowel. Alterna-
tively, total gastrointestinal perfusion(withtheinfusion
port in thestomach and theeffluent collected fromthe
rectum) canbeperformed. Toassessileal function, total
gut perfusioniscarriedout first withabalancedelectro-
lyte solution, and then a solution containing a low
concentrationof sodiumchloridecomparedwithplasma,
which requires an intact functional ileum for normal
activeabsorption.
133
Althoughthistechniquehasuncov-
ered specific absorptivedefects in patients with ileoco-
lonic resection and rare patients with idiopathic ileal
dysfunction, intestinal perfusionisnot clinicallyuseful in
most casesof chronicdiarrhea.
134
Tests for bileacid malabsorption can bedonein two
ways. Thefirst methodmeasuresthequantityof endog-
enous bile acids excreted during a quantitative stool
collection. Thesecondmethodinvolvesmeasurement of
theturnover of radiolabeledbileacid. Thiscanbedonein
twoways. Thefirst involvestheuseof agammacamerato
detect the retained fraction of an orally administered
synthetic radiolabeled bileacid, selena-homocholic acid
conjugated with taurine (commonly abbreviated
75
Se-
HCAT).
135140
Thesecondinvolvesmeasurement of fecal
recovery of an oral load of [
14
C]glycocholate during a
48- or 72-hour stool collection and calculation of a
retention half-life.
141,142
Measurement of serumconcen-
trations of an intermediate of bile acid synthesis, 7-
hydroxy-4-cholesten-3-one, is an alternate method for
evaluatingbileacidmetabolism, withareportedsensitiv-
ity and specificity of 80% and 85%, and positiveand
negativepredictivevaluesof 74%and98%, respectively,
for excessive losses of bile acids from the body.
143,144
Thesetestsarenot widelyavailabletocliniciansandhave
beencomplicatedbylack of standardizationof reference
values.
145
Furthermore, an abnormal test result is not
necessarilyspecificfor pathological bileacidmalabsorp-
tion but may occur as the result of diarrhea per
se.
141,142,146,147
Therefore, manycliniciansuseatherapeu-
tic trial of cholestyramine as an indirect test for the
possibility that malabsorbed bileacids arethecauseof
diarrhea. However, theextent towhichagoodtherapeu-
tic response to cholestyramine denotes the presence of
bileacidmalabsorptionasthemaincauseof diarrheaisan
unsettledissue.
141,142
B re a th te sts fo r p h ysio lo g ica l te stin g . Breath
testshavefoundtheir wayintoclinical diagnosismainly
for use in patients with chronic diarrhea, abdominal
bloating, or pain. The most common tests use probe
moleculeslabeledwith
14
C or
13
C
148
or anonradioactive
fermentablesugar. Metabolismof thesesubstances pro-
ducesisotopicallylabeledCO
2
or H
2
that canbedetected
inexpiredair.
149151
Thetestsandtheclinical conditions
for whichbreathtestsareusedareshowninTable3.
Te sts fo r la cto se m a la b so rp tio n . In the past,
except for therapeutic trial of a lactose-free diet, the
standarddiagnostictest for hypolactasiahadbeentheoral
lactosetolerancetest.
152
Inthistest, anoral loadof lactose
is given, followed by sequential measurement of serum
glucose. An increase in serum glucose concentration
indicatesthat lactosehasbeen hydrolyzed and absorbed
bythemucosa. However, randomfluctuationsinendog-
enousserumglucoseconcentrationslimit sensitivityand
specificity
153,154
; therefore, thelactosetolerancetest has
beenreplacedwithlactosebreathhydrogentesting. This
test exploits the fact that lactose malabsorbed by the
small intestine in lactase-deficient individuals is fer-
mented rapidly in thecolon toorganic acidsand gases,
including hydrogen.
155,156
The latter is then absorbed
and excreted by thelungs into thebreath, whereit is
collected in a balloon or bag and measured by gas
chromatographyor other methods.
Theexact methodological procedureuseddependson
whether maximal sensitivity or specificity is desired.
Tests using larger doses of lactose(e.g., 50 g) aremore
sensitivebut lessspecificfor clinicallysignificant dietary
lactoseintolerance, whereas smaller doses (e.g., 12.5 g)
aremorespecific but lesssensitive. Asacompromise, a
25-gtest doseisfrequentlyused.
Tabl e 3. BreathTests That MaybeAppliedtoPatients With
Chronic Diarrhea
Agent
administered
Substance
measured
inbreath Conditionassessed
Lactose H
2
Lactasedeficiency
Sucrose H
2
Sucrasedeficiency
Glucose H
2
Bacterial overgrowthof small
intestine
Lactulose H
2
Bacterial overgrowthof small
intestine; determinationof oro-
cecal transit time
14
C-xylose
14
C Bacterial overgrowthof small
intestine
14
C-glycocholate
14
C Bacterial overgrowthof small
intestine
1 4 7 4 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
An increase in breath hydrogen of 20 ppm above
baselinewithin4hoursusuallyhasbeenset asthecutoff
for apositivetest result, althoughStrocchi et al.
157
found
maximal diagnostic accuracy with a 12.5-g test dose
using an 8-hour test period. The lengthier test is less
practical for patients who may become irritated with
medical testsrequiringprolongedfasting. (Breathhydro-
gen testing usually requires a 12-hour pretest fasting
period to ensure that baseline fasting breath hydrogen
levelsarelow.)
As many as 10% of individuals do not possess an
intestinal bacterial floracapableof producing hydrogen
gas; theywill not produceahydrogensignal inresponse
to malabsorbed carbohydrate.
158
In such individuals, a
negativebreathhydrogentest result mayrepresent afalse
negative.
Te sts fo r b a cte ria l o ve rg ro wth . Bacterial over-
growthof thesmall intestineoccursinsomechildrenand
in someelderly adults with nonspecific gastrointestinal
complaints. Someof thesepatients donot havespecific
syndromesthat wouldpredisposethemtosuchcoloniza-
tion.
159161
Thetrueimportanceof bacterial overgrowth
of thesmall intestineas a causeof chronic diarrhea is
unknown. Cases clearly exist, especially when disorders
that diminishintestinal motilityarepresent.
162,163
The gold standard for diagnosis of bacterial over-
growth has been quantitative culture of an aspirate of
luminal fluid; more than 10
6
organisms/mL in either
aerobic or anaerobic conditions is the criterion for a
positiveculture. However, theclinical importanceof a
positivecultureisdifficult toassessbecausesomeasymp-
tomaticindividualshave10
6
organisms/mL. Neverthe-
less, inpatientswithchronicdiarrhea, apositivejejunal
culture(10
6
organisms/mL) canbeconsideredevidence
of clinicallysignificant bacterial overgrowthintheupper
small intestine. Thisevidencebecomesmorecredibleif
the patient responds to treatment with an appropriate
antibiotic.
Problems with use of jejunal cultures as a test for
bacterial overgrowth includelack of standardization of
thecollectionmethodandtherequirement for intubation
of theupper gastrointestinal tract (withanendoscopeor
fluoroscopically placed tube). Various breath tests have
been proposed as noninvasive tests for small intestinal
bacterial overgrowth. Thesetestsrelyonsomeof thesame
general principlesoutlinedintheprecedingsections.
Becausebacteriaintheupper small intestinedeconju-
gate bile acids, making them inadequate for micellar
formationandfat absorption(theprimarymechanismby
whichbacterial colonizationof thesmall intestineresults
in diarrhea), a breath test using [
14
C]glycocholate has
been developed.
164,165
Theradiolabeled conjugated bile
acidisdeconjugatedbythebacteria, andthe
14
C inthe
side chain is metabolized to
14
CO
2
, which is exhaled.
However, thistest hasnever received widespread accep-
tanceintheUnitedStates, probablybecauseof problems
withbothfalsepositives(inpatientswithileal resection
or dysfunction) and false negatives.
166,167
At least one
group of investigators overseas has reported satisfaction
withthistest, albeit almost 20yearsago.
168
Another
14
C-breathtest using[
14
C]xyloseasaferment-
ablesubstratealsohasbeenproposed. Whenaxylosedose
of 25 g was used (adosethat also allows assessment of
small bowel absorptivefunction), thetest suffered from
poor specificitybecausexyloseisnot completelyabsorbed
bythenormal small intestineandcouldreachthecolon,
where colonic bacteria could produce
14
CO
2
during a
23-hourtest period.
169
Reducingthedoseof xylosefrom
25 g to 1 g was one method of avoiding this prob-
lem.
169,170
However, sensitivity and specificity, initially
both reported to be 100%, subsequently have varied
between 65% and 90% and between 59% and 62%,
respectively.
170,171
[
14
C]Xylosebreath testing is not of-
feredat most medical centers.
Awidelyavailablealternativebreathtest usesnonradio-
activeglucoseandmeasuresbreathhydrogenexcretionas
thesignal. Inthistest, 50100gof glucoseisadminis-
tered in water by mouth, followed by measurement of
breath hydrogen concentration at 1530-minute inter-
valsfor 24hours. Becauseevenadiseasedsmall intestine
shouldbeabletoabsorbthisloadof glucosecompletely,
false-positiveresults(fromcolonic fermentation) should
belessfrequent thaninteststhat use25gof xylose. An
increasein breath hydrogen concentration of morethan
1220ppmabovebaselineisconsideredapositiveresult.
As in other breath tests, sensitivity and specificity vary
widely, inthiscasefrom62%to93%andfrom78%to
100%, respectively.
167,172,173
Another breathtest usingnonradioactivelactulosealso
hasbeenused. Inthisversion, breathhydrogenexcretion
ismonitoredafter ingestion. Althoughit wouldseemto
have the same limitations as xylose in that colonic
fermentationwouldresult inalowspecificity(e.g., 44%
in onestudy
173
), 100%specificity hasbeen reported.
174
Thisconclusion istentativebecause, asin most clinical
studies of breath tests, thenumber of patients enrolled
wasrelativelysmall.
Anelevatedconcentrationof hydrogeninbreathafter
overnight fastingalsohasbeenproposedasaninsensitive
but specific marker of small intestinal bacterial over-
growth.
172,175
Thiselevatedhydrogenconcentrationmay
alsobeseeninpatientswithmalabsorptionsyndrome.
Finally, an abnormal Schilling II test result (radiola-
beled B
12
given with intrinsic factor) that normalizes
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 7 5
after therapy with broad-spectrumantibiotics has also
been considered as a test for small intestinal bacterial
overgrowth(theso-calledSchillingIII test).
176,177
How-
ever, this approach is indirect because it requires a
positive result fromparts I or II of the Schilling test
beforeit canbeapplied, andinmanycasesit evolvesout
of investigation of vitamin B
12
deficiency rather than
diarrheaper se. Theclinical utility of thisapproach has
not beentested.
Te sts o f p a n cre a tic e xo crin e fu n ctio n . Intuba-
tion tests are still considered the gold standards for
pancreaticfunctiontesting. Inthesetests, atubeisplaced
under fluoroscopic guidancewith an aspiration port in
thedistal duodenum; another port isusedtodraingastric
juicefromthestomach. After secretinand/or cholecysto-
kininisadministeredintravenously
178180
oratest meal is
eaten,
181,182
duodenal fluidisaspiratedfor measurement
of bicarbonateconcentration and output and pancreatic
enzymelevels. Althoughthesetestsaretime-honoredand
direct intheir principles, theyrequireintestinal intuba-
tion, andseveral technical difficultieslimit their applica-
tion. Theseincludetheneedfor correct placement of the
drainagetubeandadequateaspirationof duodenal fluid,
contaminationof fluidbybileandgastricjuice, theneed
for accurateassayof thefluidfor bicarbonateandenzyme
concentrations, andtheneedtoestablishclinicallyuseful
limitsof normal and abnormal. Thisformof pancreatic
functiontestingrarelyisdoneanymore.
Several noninvasivetests of pancreatic exocrinefunc-
tion havebeen developed tomakethis evaluation more
acceptable to patients and physicians. Two types have
receivedsomedegreeof acceptance, thebentiromidetest
andmeasurement of pancreaticenzymesinstool.
Thebentiromidetest reliesonthepresenceof enough
chymotrypsin in the duodenal lumen to digest the
peptidebond in thebentiromidereagent (N-benzoyl-L-
tyrosyl-p-aminobenzoic acid). This releases para-amino-
benzoic acid, which is absorbed by the mucosa and
excretedintheurine.
183185
Urinaryexcretionof lessthan
85 mg of para-aminobenzoic acid (50% of theamount
containedin500mgof bentiromide) in6hourshasbeen
set asthethresholdfor apositivetest result.
184
Aswith
other testsinvolvingurinaryexcretionof atest substance,
renal insufficiencyandthepotential for incompleteurine
collection are confounding factors capable of causing
false-positiveresults (i.e., reducing urinary recovery for
reasons unrelated toinadequatepancreatic function). In
one study, the sensitivity of the test was 80%; the
specificitywas95%.
184
Because of their simplicity and diagnostic accuracy,
measurements of fecal concentrations of the pancreatic
enzymeschymotrypsin, trypsin, lipase, andelastasehave
beendevelopedastestsof pancreaticfunction.
186190
The
fecal chymotrypsintest hasbeenthemost widelyapplied.
Itssensitivityisapproximately80%, but itsspecificityis
approximately 90%, perhaps becauseof problems with
preservation of the enzymes activity during intestinal
transit or after itspassageanddilutionof theenzymeby
fecal water inthesettingof diarrhea. Althoughcalcula-
tion of output seemingly would solvetheproblemof
dilution, the method involves measurement of the en-
zymes activity rather than its true concentration; this
mayexplainwhycalculationof output bymultiplication
bystool weight provedtobelessaccuratethanconcentra-
tioninonestudy.
191
The newest in a long line of enzymatic tests of
pancreaticfunctionismeasurement of theconcentration
of theenzymeelastaseinfecesusinganELISAmethod.
190
In this test, theamount rather than theactivity of the
enzyme is measured and is expressed in concentration
terms(usuallymicrogramsof enzymeper gramof stool).
Inacomparativestudy, fecal elastaseoutperformedfecal
chymotrypsinintermsof bothsensitivityandspecificity.
However, likeall of itspredecessors,
192
measurement of
fecal elastasemust standthetest of time.
Breath tests have been developed for determination
of exocrine pancreatic insufficiency using [
14
C]tri-
olein.
193195
Detection of
14
CO
2
in expired air requires
sufficient pancreatic lipase activity to hydrolyze the
labeledfattyacidfromitsglycerol backbone, absorption
of thefattyacidbythesmall intestinal mucosa, metabo-
lismof thelabeled fatty acid to
14
CO
2
in thebody, and
excretion of
14
CO
2
in thebreath. Thusabnormalitiesof
small intestinal absorption, fatty acid metabolism, and
pulmonaryfunctioncouldinterferewiththeappearance
of theisotopeinbreath, evenif pancreaticfunctionwere
normal. Perhaps for these reasons, the promise and
excitement accompanying early reports of this method
havewanedover theyears. A newmodificationof breath
testing for assessment of fat absorption that combines
moreintense
14
Clabeling, useof auniquefattyacid, and
a dual method that separates digestive and absorptive
functionwasreportedrecentlyinabstract form.
196
More
informationabout theclinical utilityof thistest must be
obtained.
Te sts fo r G a stro in te stin a l F o o d Alle rg y
Allergy to food antigens may be the cause of
chronicdiarrheainsomepatients, but documentationof
thishasbeendifficult. Reportshavedescribeddetection
of antibodies to food in feces
197,198
or small intestinal
secretions.
199
Validation studies in larger groups of
patientswithchronicdiarrheaareneededbeforethevalue
of these tests is apparent. Serumantibody testing and
1 4 7 6 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
skin testing are not of proven value in detection of
gastrointestinal foodallergies.
Recommended Approach t o Pat i ent s
Wi t h Chroni c Di arrhea
Systematic outcomesresearch toevaluatevarious
clinical approaches to chronic diarrhea has not been
reported. Publicationsrelevant tomanagement areof two
types: recommendationsbyexpertsinformedbyclinical
experience
14,200205
andreportsof seriesof patientswith
chronicdiarrheafrommedical centerswithaninterest in
thisproblem.
15,16,115,206,207
Bothtypesof publicationsare
subject toreferral biasandmayor maynot beapplicable
to patients with chronic diarrhea seen in different
settings. Thefollowing recommendations represent our
synthesis of this information as colored by our clinical
experience(Figures1and2).
M e d ica l H isto ry
Somespecificsof athoroughmedical historycan
guideappropriateevaluationof thepatient withchronic
diarrhea (Table 4). First, it must be understood what
specific symptoms haveled thepatient to complain of
diarrhea(e.g., stoolsaretoolooseor watery, fragment in
the toilet, are too frequent, or are associated with
urgency). Detailedquestioningabout all characteristicsof
thestools themselves is anecessity. Although aspecific
diagnosisrarelyisproducedbythislineof questioning,
the information helps the physician understand the
magnitudeof theproblemandallowsthepatient toknow
that hisor her problemisbeingtakenseriously. Patients
sometimesareembarrassedbydiscussingdiarrhea, particu-
larly if fecal incontinence is present. This symptom
shouldalwaysbeinquiredabout directlybecauseit rarely
isvolunteered.
Fi gure 1. Flowchart ormindmap forevaluationof chronicdiarrhea. Initial efforts shouldbedirectedtoclassificationof chronicdiarrheabased
onhistory, physical examination, basiclaboratorytest results, andstool analysis.
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 7 7
Thecharacteristicsof thestool maysuggest apotential
pathophysiological mechanism(e.g., malodorous, float-
ing, greasy stools containing food particles suggesting
malabsorption; or gross blood suggesting inflammation
or neoplasm). Thepatientsperception of thevolumeof
diarrheamay help to localizethediseaseprocess in the
gastrointestinal tract. Diarrheathat iswateryandvolumi-
noussuggestsadisorder of thesmall bowel or proximal
colon, whereas frequent, small-volumediarrheamay be
associatedwithdisordersof theleft colonor rectum. The
latter disorders areoften accompanied by tenesmus and
passageof dark, mushy stools that may contain mucus,
pus, or blood.
Fever or weight loss may herald a diagnosis of
inflammatory bowel disease, amebiasis, intestinal lym-
phoma, othermalignancies, Whipplesdisease, tuberculo-
sis, other entericinfections, or thyrotoxicosis.
The patients medical history may be important.
Seronegativespondyloarthropathymayprecedetherecog-
nition of inflammatory bowel diseaseby many years. A
historyof diabetes, thyroidproblems, andother autoim-
munephenomenamaybepertinent. Previoussurgeryto
thegastrointestinal or biliarytractsmaybethecauseof
diarrhea. Other diseasesassociatedwithdiarrheainclude
rheumatic diseaseswith or without vasculitis, immuno-
globulindeficiency, andpepticulcer diseaseif causedby
theZollingerEllison syndromeor systemic mastocyto-
sis.
All current medications(includingover-the-counter
drugs), nutritional supplements, illicit drugs, alcohol,
Fi gure 2. Flowcharts or mindmaps for further evaluationof secretorydiarrhea (topleft), osmotic diarrhea (topright), inflammatorydiarrhea
(lower left), and fatty diarrhea (lower right). It is not necessary to performevery test in a given pathway once a diagnosis is reached. TSH,
thyroid-stimulatinghormone; ACTH, adrenocorticotropichormone; 5-HIAA, 5-hydroxyindoleaceticacid.
1 4 7 8 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
andcaffeineusedbythepatient shouldbenoted. Patients
shouldbeaskedspecificallyabout newmedicines, magne-
sium-containing products, and any antibiotics taken
withinthepreceding68-weekperiod.
A detailed dietary history should be obtained with
special attentiontorecent changes; special diets; sugar-
free foods, gums, or mints (which may contain poorly
absorbablesugar alcohols); fiber intake; andconsumption
of rawseafoodor shellfish. Thepatientsusual intakeof
fruits, fruit juices, vegetables, milk products, andbever-
agescontaining high concentrationsof sugar or caffeine
shouldalsobeestimated.
Thefamilyhistorymaydiscloseotherswithdiarrheaor
familial diseasesassociatedwithdiarrhea, suchascongeni-
tal absorptivedefects, inflammatorybowel disease, celiac
sprue, IBS, and multipleendocrineneoplasia. A careful
social history should be obtained including details of
recent travel, type of residential area (urban vs. rural),
livingconditions, sourcesof drinkingwater, occupation,
sexual preference, and sexual activity. Patients living in
rural settings may beexposed tofarmanimals that can
harbor bacterial pathogens (such as Salmonella or Bru-
cella). Consumption of well water or rawmilk alsomay
causeinfections, sometimesassociatedwithepidemicsof
chronicdiarrhea. Health-careworkersmaybeat risk for
nosocomial entericinfections(includingClostridiumdiffi-
cile) andfactitiousdiarrhea. A discretebut direct inquiry
into thepatients sexual practices must bemade. Anal
intercourseisarisk factor for proctitisduetogonorrhea,
herpes simplex, Chlamydia, syphilis, and amebiasis, as
well as routine bacterial pathogens. Promiscuous or
unprotected sexual activity is a risk factor for HIV
infectionandthemultitudeof causesof diarrheaassoci-
ated with the acquired immunodeficiency syndrome
(AIDS).
200205
Becausefunctional disordersareverycommonandmay
be associated with diarrhea, factors suggestive of IBS
should besought. Theseincludealong history (usually
beginninginthesecondor thirddecade) of intermittent
abdominal painassociatedwithalterationof bowel habits
(classically diarrhea alternating with constipation or
passageof pellet-likestools), passageof nonbloody mu-
cus, and symptoms exacerbated by emotional stress.
Factorsthat argueagainst IBSincludearecent onset of
diarrheawithout along history (especially in amiddle-
agedor older person), lack of abdominal pain, nocturnal
diarrhea (especially if associated with incontinence),
weight loss (particularly greater than 510 pounds),
stools containing gross or occult blood, fecal weight
greater than 400500 g/day, and abnormal blood test
results (e.g., low hemoglobin, low albumin, or high
erythrocyte sedimentation rate).
15,16,208,209
Finally, it is
important to determinewhether thepatient is seeking
help mainly because of fear of a potentially dangerous
problem (such as cancer) or primarily for relief of
symptoms.
P h ysica l E xa m in a tio n
In most cases of chronic diarrhea, results of
physical examination are normal or nondiagnostic. In
some cases, however, important clues to the diagnosis
may be found including mouth ulcers, signs of severe
atherosclerosis, lymphadenopathy, signs of autonomic
failure, andrashes, flushing, or hyperpigmentationof the
skin. It is important todeterminethevolumestatus of
the patient; in all instances, it is more important to
correct dehydration and electrolyte depletion than to
establishadefinitivediagnosis.
Tabl e 4. Implications of SomeAspects of Medical History
Lineof questioning Clinical implication
Onset
Congenital Chloridorrhea, Na

malabsorption
Abrupt Infections, idiopathic secretory
diarrhea
Gradual Everythingelse
Familyhistory Congenital absorptivedefects,
IBD, celiac disease, multiple
endocrineneoplasia
Dietaryhistory
Sugar-free foods Sorbitol, mannitol ingestion
Rawmilk Brainerddiarrhea
Exposuretopotentiallyimpure
water source
Chronic bacterial infections (e.g.,
Aeromonas), giardiasis, crypto-
sporidiosis, Brainerddiarrhea
Travel history Infectious diarrhea, chronic idio-
pathic secretorydiarrhea
Weight loss Malabsorption, pancreatic exo-
crineinsufficiency, neoplasm,
anorexia
Previous therapeutic interven-
tions (drugs, radiation,
surgery, antibiotics)
Drugsideeffects, radiation
enteritis, postsurgical status,
pseudomembranous colitis
Secondarygainfromillness Laxativeabuse
Systemic illness symptoms Hyperthyroidism, diabetes,
vasculitis, tumors, Whipples
disease, IBD, tuberculosis,
mastocytosis
Intravenous drugabuse,
sexual promiscuity
AIDS
Immuneproblems AIDS, Igdeficiencies
Abdominal pain Mesenteric vascular insufficiency,
obstruction, IBS
Excessiveflatus Carbohydratemalabsorption
Leakageof stool Fecal incontinence
Stool characteristics
Blood Malignancy, IBD
Oil/ foodparticles Malabsorption, maldigestion
White/ tancolor Celiac disease, absenceof bile
Nocturnal diarrhea Organic etiology
J u n e 1 9 9 9 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N 1 4 7 9
F u rth e r E va lu a tio n
Insomecases, findingsfromthepatientshistory
and physical examination may point strongly to a
particular diagnosis, andspecific, confirmatorytestscan
be ordered or a trial of empirical therapy may be
warranted. In many cases, particularly thosein which a
partial evaluation has already been carried out without
definingadiagnosis, aquantitativestool collectionisthe
best choicefor further evaluation. Thisallowsapprecia-
tion of stool weight, examination for the presence or
absenceof steatorrhea, andclassificationof anosmoticor
nonosmotic (secretory) process. Thesecharacteristics, in
combination with facets of the history and physical
examination, can narrow down the possible diagnoses
(Table5). Thediagnosticevaluationthencanbedirected
inanefficient fashion. Althoughthisapproachisrational,
it hasnot beentestedformallyinpracticeor byclinical
simulation. Theefficacyof repeatedevaluationsalsohas
not been studied. In our opinion, there is little to be
gained from repeated investigations once a thorough
evaluationhasbeenconcluded.
Empi ri cal Therapy of Chroni c
Di arrhea
Empirical therapyisusedinthreesituations: (1)as
temporizing or initial treatment beforediagnostic test-
ing, (2) after diagnostic testing has failed to confirma
diagnosis, and (3) when adiagnosishasbeen made, but
no specific treatment is available or specific treatment
fails toeffect acure. An empirical trial (e.g., antibiotic
therapy) could be considered as initial therapy if the
prevalenceof bacterial or protozoal infectionishighina
community or in aspecific situation. A successful trial
wouldeliminatetheneedfor amoreextensiveevaluation.
For example, a case of chronic diarrhea in a daycare
worker might betreatedempiricallywithmetronidazole
for suspected giardiasis. No utility analysis of this
approachisavailablefor most situationslikelytobefaced
intheUnitedStates. OnestudyfromMexicopublished
in1974studiedtheeffectivenessof empirical amoxicillin
inthetreatment of chronic diarrheainpatientsof low
socioeconomic status; 96% were asymptomatic by the
third day.
210
It is unlikely that similar success would
meet empirical antibiotictherapyinmost patientswith
chronic diarrhea in the United States, because chronic
diarrheaislesslikelytobecausedbybacterial infectionin
theUnitedStates.
Symptomatictherapyforundiagnosedorpoorlyrespon-
sivechronic diarrheacan involveavariety of agents.
211
Natural andsyntheticopiatesarethemost widelyused,
but other agents, such as bile acidbinding agents,
bismuth, andmedicinal fiber, aresometimesused. Many
of theseagentswereintroducedtomedicinebeforetheera
of randomized, controlled trials, and only the most
modernhavebeenthesubjectsof proper studies. Never-
theless, aconsiderablebodyof experienceguidestheuse
of theseagents.
Opium has been used for 2500 years to control
diarrheaandremainsahighlypotent remedy. Most cases
of diarrhea, except for high-volume secretory states,
respondtoasufficientlyhighdoseof opiumor morphine.
Codeine is somewhat less potent, and the synthetic
opioids diphenoxylate and loperamide are clearly less
potent. Becauseof thepotential for abuse, thesedrugs,
with the exception of loperamide, are controlled sub-
stances in theUnited States. In practice, patients with
Tabl e 5. Major Causes of Chronic DiarrheaClassifiedby
Typical Stool Characteristics
Osmotic diarrhea Secretorydiarrhea
Mg
2
, PO
4
3
, SO
4
2
ingestion
Carbohydratemalabsorption
Fattydiarrhea
Malabsorptionsyndromes
Mucosal diseases
Short bowel syndrome
Postresectiondiarrhea
Small bowel bacterial over-
growth
Mesenteric ischemia
Maldigestion
Pancreatic exocrineinsuffi-
ciency
Inadequateluminal bileacid
Inflammatorydiarrhea
Inflammatorybowel disease
Ulcerativecolitis
Crohns disease
Diverticulitis
Ulcerativejejunoileitis
Infectious diseases
Pseudomembranous colitis
Invasivebacterial infections
Tuberculosis, yersinosis,
others
Ulceratingviral infections
Cytomegalovirus
Herpes simplex
Amebiasis/ other invasive
parasites
Ischemic colitis
Radiationcolitis
Neoplasia
Coloncancer
Lymphoma
Laxativeabuse(nonosmotic
laxatives)
Congenital syndromes (chlor-
idorrhea)
Bacterial toxins
Ileal bileacidmalabsorption
Inflammatorybowel disease
Ulcerativecolitis
Crohns disease
Microscopic (lymphocytic)
colitis
Collagenous colitis
Diverticulitis
Vasculitis
Drugs andpoisons
Disorderedmotility
Postvagotomydiarrhea
Postsympathectomydiarrhea
Diabetic autonomic neu-
ropathy
Hyperthyroidism
IBS
Neuroendocrinetumors
Gastrinoma
VIPoma
Somatostatinoma
Mastocytosis
Carcinoidsyndrome
Medullarycarcinomaof thy-
roid
Neoplasia
Coloncarcinoma
Lymphoma
Villous adenoma
Addisons disease
Epidemic secretory(Brainerd)
diarrhea
Idiopathic secretorydiarrhea
1 4 8 0 AM E R I C AN G AS TR O E N TE R O LO G I C AL AS S O C I ATI O N G AS TR O E N TE R O LO G Y Vo l. 1 1 6 , N o . 6
chronic diarrhea seldom abuse these agents, and it is
unusual torequireever higher dosestocontrol diarrhea
once an effective dose is reached. Potent narcotics are
probably underused in the treatment of severe chronic
diarrhea. Lesser opioids, such as diphenoxylate and
loperamide, are satisfactory for control of less severe
diarrheaand ought tobetried beforeresorting tomore
potent drugs. Theprodrug loperamide-N-oxideand the
enkephalinase inhibitor acetorphan are under develop-
ment and may have some therapeutic advantages over
currentlyavailableagents.
212214
Thesomatostatinanalogueoctreotidehasproveneffec-
tivenessincarcinoidtumorsandother peptide-secreting
tumors, dumpingsyndrome, andchemotherapy-induced
diarrhea. It has had limited success in patients with
AIDS-associated diarrheaand short bowel syndrome.
211
Octreotide does not seem to have any advantage over
opiates in thetreatment of chronic idiopathic diarrhea
and probably should be a second-line agent for this
indication because of the need for administration by
injectionanditsexpense.
Intraluminal agentsincludeadsorbants, suchasclays,
activatedcharcoal, andbindingresins; bismuth; andstool
modifiers, such as medicinal fiber.
211
Few controlled
studies have been conducted with these agents, and
results have been equivocal. Cholestyramine and other
similar binding resins have reduced stool weight in
European studies in which patients with chronic idio-
pathic diarrheahavehad ahigh frequency of bileacid
malabsorption.
135139,215
InanAmericanseries, cholestyr-
aminehadlittleeffect inthesepatients, evenwhenbile
acidmalabsorptionwaspresent.
141
Bismuthsubsalicylate
hasbeenshowntobeeffectiveinacutetravelers diarrhea,
but its effectiveness in chronic diarrheais unproven.
216
Stool modifiers, suchaspsyllium, mayalter stool consis-
tencybut donot reducestool weight.
217
Oral rehydration solutions that include glucose or
other nutrients and salt areuseful for repletion of body
fluids.
211
Cereal-based oral rehydration solutions have
gainedacceptanceinrecent years. Theycanbelife-saving
therapyfor dehydrating, acutesecretorydiarrheas, suchas
cholera, but have limited application in most chronic
diarrheal statesand havenot been well studied in these
situations. Althoughthesesolutionsincreasenet salt and
water absorption, they arenot designed to reducestool
weight, and diarrhea (defined by stool weight or fre-
quency) mayworsenwiththeir use.
Di rect i ons f or Fut ure Research
Studyof clinical outcomesinpatientswithchronic
diarrhea has been fragmentary. Utility parameters are
availablefor somediagnostictests, but intheabsenceof
solidepidemiological dataabout theprevalenceof differ-
ent causes of chronic diarrhea, thesecannot beapplied
accuratelytoclinical decisionmaking. Algorithmicman-
agement isuntested, andtheeconomicaspectsof differ-
ent approachestothediagnosisandtreatment of chronic
diarrhea are unstudied. Opportunities for clinical re-
searchinpatientswithchronicdiarrheaarevoluminous.
KENNETH D. FINE
LAWRENCER. SCHILLER
GastroenterologySection
Department of Internal Medicine
Baylor UniversityMedical Center
Dallas, Texas
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e d g e s th e fo llo win g in d ivid u a ls wh o se critiq u e s o f th is re vie w p a p e r
p ro vid e d va lu a b le g u id a n ce to th e a u th o rs: M a rk D o n o witz, M . D . ,
J e ffre y L. B a rn e tt, M . D . , a n d D o n W. P o we ll, M . D .

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