Comparison of 24-h and overnight samples of urinary 5-hydroxyindoleacetic acid in patients with intestinal neuroendocrine tumors.

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by  Gedde-Dahl, Merete

MGedde-Dahletal. 24-hvs.w8-hurinary5-HIAA 1–5 2:50
Research
OpenAccess
Comparison of 24-h and
overnight samples of urinary
5-hydroxyindoleacetic acid in
patients with intestinal
neuroendocrine tumors
MereteGedde-Dahl,EspenThiis-Evensen,AndreasMyklebustTjølsen1,
KjerstinSkredeMordal,MortenVatnandDeidiSBergestuen Correspondence
shouldbeaddressed
SectionofGastroenterology,DepartmentofTransplantationMedicine,OsloUniversityHospital,Rikshospitalet, toMGedde-Dahl
Postboks4953,Nydalen,0424Oslo,Norway Email
1UniversityofOsloSchoolofMedicine,Oslo,Norway [email protected]
s
n Abstract
o
ti
c
ne Neuroendocrinetumors(NETs)arisinginthesmallintestineareknowntoproducevasoactive
n
o substances,includingserotonin,thatmayresultinthecarcinoidsyndrome(flushing,
C
ne diarrhea,bronchoconstriction,andcarcinoidheartdisease).Measurementoftheserotonin
ri
oc breakdownproduct5-hydroxyindoleaceticacid(5-HIAA)inurineisimportantindiagnosing
d
n andmonitoringofpatientswithintestinalNETs.Ouraimwastocompare5-HIAA
E
measurementin24-hurinesamplingwithovernight(w8-h)samplinginpatientswith
knownNETs,oratfollow-upofpatientspotentiallycuredfortheirNETs.Twenty-four-hour
andovernighturinesampleswerecollectedfrom34patientsandanalyzedforurinary
5-HIAA(U5-HIAA)usingHPLC.Comparisonoftheovernightsamplingvalueswiththe24-h
valuesshowednodifference,PZ0.45,andtherewasasignificantdirectcorrelationbetween
thetwosamplesusinglinearregression(RZ0.97,P!0.001).U5-HIAAsamplecollection
duringanightlyintervalofw8happearstohavethesameaccuracyasthe24-hcollection
inthisgroupofpatients.
EndocrineConnections
(2013)2,50–54
Introduction
Gastroenteropancreatic neuroendocrine tumors (NETs) bronchospasm. The syndrome is almost exclusively seen
are rare tumors of the gastrointestinal tract arising from inpatientswithlivermetastases,ormetastasesoutsidethe
cellsoftheneuroendocrinesystem.Thesecellsareknown abdominal cavity, as serotonin and other secretory
for their capacity to produce various peptides and products from the primary tumor are metabolized in the
hormones with endocrine functions (1). Small intestinal liver at first pass. Reportedly, 10–18% of patients with
NETs often produce vasoactive substances that may smallintestinalNETshavecarcinoidsyndrome(1,2).
result in the carcinoid syndrome, symptoms of which Serotonin(5-hydroxytryptamine)isthoughttoplaya
include flushing, diarrhea, carcinoid heart disease, and majorroleinthedevelopmentofthecarcinoidsyndrome
http://www.endocrineconnections.org (cid:1)2013TheAuthors.PublishedbyBioScientificaLtd.ThisisanOpenAccessarticle
DOI:10.1530/EC-12-0077 distributedunderthetermsoftheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedthe
originalauthorandsourcearecredited.
Research MGedde-Dahletal. 24-hvs.w8-hurinary5-HIAA 2–5 2:51
(1, 3, 4). Biochemically, serotonin is derived from the U5-HIAA.ToanalyzeU5-HIAAinboth24-handovernight
essentialaminoacidtryptophanandisprimarilyfoundin urinesamples,thesamplingprotocolwaschangedforthe
the gastrointestinal tract (5). In the blood, serotonin is last 34 included patients. These 34 consecutive patients
quicklytakenupbytheplatelets(6)andlatermetabolized, wereincludedinthisstudy.
mainly in the liver, in two oxidation steps, resulting The study was approved by the regional ethics
in 5-hydroxyindoleacetic acid (5-HIAA) as the main committee, and all participants signed a written consent
degradationproduct(5).5-HIAAisthenreleasedintothe accordingtotheHelsinkideclaration.
bloodstreamandexcretedbythekidneys(7).
Serummeasurementofserotoninispossible,butlarge
Urinarysampling
individual variation makes this measurement unreliable
(8). Urinary 5-HIAA (U5-HIAA) has less biological vari- All urine samples were obtained during hospitalization
ationandisthereforeconsideredmoreusefulindiagnosis andthecollectionwasmonitoredbynursestrainedinthe
andfollow-upofpatientswithNETs.
procedure.Nofoodanddrugrestrictionsweregiven.The
Inadditiontoitsvalueindiagnosisandfollow-upof
samplingstartedafterthefirstmorning’surinewasvoided
patients with NETs (2, 9, 10), U5-HIAA is also associated
and ended by adding next morning’s urine to the
with prognosis (11, 12). Twenty-four-hour U5-HIAA
collection container. Before the next morning’s urine
measurement has a reasonable sensitivity (73%) and up
wasaddedtothecontainer,afewmilliliterswereextracted
to100%specificityforNETs(8,10,13,14).The24-hurine
and analyzed separately. During the 24-h collection, the
samplecollectioncan, however,betroublesomefor both
time of the last urination before bedtime and the first
patients and health care professionals and is often
morning urine was recorded. The 24-h collections
performed incorrectly. It requires multiple urine collec-
were stored in containers in which 10ml 2mol HCl had
ns tions during the 24-h period and bulky transport of the
o beenadded.
ti sample container(s), with potential social limitations for
c
e
n the patient during the collection. Acidification of the
n
o
C urineisrequiredtomaintainstableandsterileconditions Analysis
e
n in the collection container. Easier methods to monitor
cri AllsampleswhereacidifiedtopH4with6molHClbefore
o U5-HIAAlevelsarethuswarranted.
nd analyses were performed at the Department of Medical
E Zuetenhorst et al. (6) investigated the daily variation
Biochemistry at Oslo University Hospital, Rikshospitalet,
inU5-HIAAsecretionin4-and8-hincrementsandfound
using HPLC with electrochemical detection, with a kit
that the overnight interval (2300–0700h) was most
from Chromosystems (Munich, Germany). U5-HIAA was
representativeforthe24-hsecretion.Wethereforewanted
measured as mmol/mmol creatinine. The normal range is
to compare the results from an overnight U5-HIAA
0.9–3.8. The lowest detectable value was 0.5mmol/mmol
sampling with results from 24-h U5-HIAA sampling in a
creatinine.
well-characterized populationof patients, either at work-
up of known NETs or at follow-up after surgery with
curativeintent. Statisticalanalysis
Differences between groups are given as median and
Materials and methods range. Related samples Wilcoxon signed rank test was
used to compare the sets of paired U5-HIAA samples.
Patients
Linear regression analysis was applied to evaluate corre-
Ninety-two consecutive patients with histologically lationbetweenthepairedsamplesandbetween24-hand
verified small intestinal (nZ89), appendiceal (nZ2), or overnight collections. As the U5-HIAA values were not
proximal colonic (nZ1) NETs were admitted to the normally distributed, the values were plotted using a
gastroenterology ward at Oslo University Hospital, Rik- logarithmic scale. To be able to use all samples in the
shospitalet,betweenSeptember1,2006andSeptember1, statisticalanalyses,sampleswithvaluesbelowthedetect-
2007, either for first time evaluation or follow-up after ablethresholdof0.5weregiventhevalue0.1mmol/mmol
medical or surgical treatment. These patients were creatinine. Statistical analysis was performed using SPSS
includedinastudytoinvestigatetherelationofcarcinoid 18.0 software (SPSS, Inc.). P values are two sided and
heart disease to several biomarkers (15, 16), including consideredsignificantwhen!0.05.
http://www.endocrineconnections.org (cid:1)2013TheAuthors.PublishedbyBioScientificaLtd.ThisisanOpenAccessarticle
DOI:10.1530/EC-12-0077 distributedunderthetermsoftheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedthe
originalauthorandsourcearecredited.
Research MGedde-Dahletal. 24-hvs.w8-hurinary5-HIAA 3–5 2:52
Table1 Patientcharacteristics. regression, a significant direct correlation between the
24-handtheovernightsamplevaluesforthetotalgroup
Totalgroup(nZ34) wasdemonstrated(RZ0.97,P!0.001)(Figs1and2).The
Gender patients with no detectable tumors had a median 24-h
Men 18(52.9%) sampling value of 3.4 (range 0.1–10.7) and an overnight
Women 16(47.1%) samplingmedianof3.1(range1.1–10.1).Thecorrespond-
ing results for the patients with known tumors were 8.2
Age,years(median,range) 62(18–76)
(0.1–89) and 7.8 (1.0–94) respectively. The eight patients
Primarytumorlocation
using sustained release serotonin analogs (lanreotide or
Smallintestine 33(97.1%)
octreotide)hadamedianof15.6(range1.0–27.9)and14.6
Appendix 1(2.9%)
(range1.0–31.5)forthe24-handtheovernightsamplings.
Knownremainingtumor 24(71%)
Diseasedistribution
Discussion
Local/regionalmetastases 5/24(21%)
Distantmetastasesa 19/24(79%) Our results show a significant correlation between 24-h
Somatostatinanaloguse 8(23.5%) and overnight U5-HIAA values in this cohort of patients
Overnightsamplingperiod(h) 8.3(7–10) with prior or present NETs of small intestinal or
MedianU5-HIAA,24h 6.5(0.1–246)b appendiceal origin. This suggests that a U5-HIAA sample
collectedduringanightlyintervalofw8hmayreplacethe
MedianU5-HIAA,8h 5.4(1.0–209)b
established 24-h collection for follow-up of these patient
s aLiver,bone,andlymphglandsoutsidetheabdominalcavity(range). groups. An overnight sampling would be less time-
on bmmol/mmolcreatinine. consumingandreducetheriskofsamplingerrors.
ti
ec This procedure would, however, be susceptible to a
n
n diurnalvariationinU5-HIAAsecretion.Dailyvariationin
o Results
C
e U5-HIAA secretion was investigated by Zuetenhorst et al.
n
ri Patients They measured U5-HIAA in 4- and 8-h increments and
c
o
d foundthatpatientsfallintotwocategories,onewithlittle
n The patient population consisted of 18 men and 16
E
women, with a median age of 62 (range 18–76) years.
Thirty-threepatientshadsmallintestinalNETs,whileone
patient had a NET originating from the appendix. After
1000
previoussurgicaltreatment,ten(29%)ofthepatientswere
regarded as cured, as no residual tumors were detected
on two-phase (arterial and portal venous) computed
tomography. Twenty-four (71%) patients had detectable Cr 100
tumors (Table 1). In four patients, both 24-h and over- ol
m
nightsamplingwasperformedtwice;hence,atotalof38 m
pairedvalueswereavailableforthecomparisonstatistical mol/ 10
µ
analysis.Mediancollectiontimefortheovernightsample A
A
was8.3(range7–10)h.Collectiontimeswerenotavailable HI
5-
forthreeofthepatients. U 1
OvernightU5-HIAAvaluescomparedto24-hU5-HIAA
0.1
values
24 h Overnight
Measurements of 24-h samples of U5-HIAA (median 6.5
(range0.1–246)mmol/mmolcreatinine)werecomparedto Figure1
measurementsofovernightsamplesofU5-HIAA(median Correlationof24-htoovernightsamplingofU5-HIAA.U5-HIAAvaluesare
plottedonthey-axisusingalogarithmic(log10)scaleduetonon-normal
5.4 (1.0–209) mmol/mmol creatinine). No difference was
distributionoftheresults.Thedottedlinesrepresentpatientswithno
detected between the samples, PZ0.45. Using linear detectabletumorsandthefulllinesrepresentpatientswithknowntumors.
http://www.endocrineconnections.org (cid:1)2013TheAuthors.PublishedbyBioScientificaLtd.ThisisanOpenAccessarticle
DOI:10.1530/EC-12-0077 distributedunderthetermsoftheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedthe
originalauthorandsourcearecredited.
Research MGedde-Dahletal. 24-hvs.w8-hurinary5-HIAA 4–5 2:53
overnight/8-h sampling may very well exclude the need
1000 for acidification. However, further research is needed to
verify this. Serotonin levels, and consequently U5-HIAA
levels,areinfluencedbycertainfoodanddrugs(4).Hence,
100 the European Neuroendocrine Tumor Society Consensus
A
A Guidelinesrecommendthatpatientsfollowfoodanddrug
HI
5- restrictions for 3 days before urine collection (8).
U
ht 10 A limitation of this study is that no food and drug
g
ni restrictions were given to the patients. However, as any
er
v drugs or food items affecting the U5-HIAA levels would
O
1 most likely influence both the overnight and the 24-h
results in the same patient, we do not believe such
restrictions would significantly alter the relationship
0.1 betweenovernightand24-hresultsinthisstudy.
0.1 1 10 100 1000
The resultsfrom overnight samplingarebasedon an
24 h U5-HIAA
‘in body sampling time’ of about 8h; hence, if patients
urinate frequently during the night, all this urine
Figure2
willhavetobesampledtomaintaina collectioninterval
Scatterplotshowingthedirectcorrelationbetweenpaired24-hand
overnightU5-HIAAsamples.U5-HIAAvaluesareplottedonthex-and of w8h.
y-axesusinglogarithmic(log10)scalesduetonon-normaldistributionofthe Somatostatin analog treatment is known to reduce
results.Theopencirclesrepresentpatientswithnodetectabletumorsandthe
U5-HIAAlevels(20).Theimpactofsuchtreatmentonthe
s blackcirclesrepresentpatientswithknowntumors(RZ0.97,P!0.001).
n
o cyclic variation of 5-HIAA is not known. In our small
ti
ec sample of eight patients using sustained release somato-
n variation in U5-HIAA levels during 24h and one with
n
o statinanalogs,wesawnodifferenceintheresultsbetween
C morevariation.Thepatientswithapronouncedvariation
e the24-handtheovernightsamples.Wewouldnotexpect
n had a peak in the morning interval (0700–1100h) and a
cri anysignificantvariationsinU5-HIAAlevelsastheserum
o dip in the evening interval (1900–2300h). Overall, they
End foundtheovernightinterval(2300–0700h)tobethemost level of sustained release somatostatin analog formu-
lationsshowsverylittledailyfluctuation(21).Ourresults
representative for the 24-h secretion. The authors specu-
should,however,bereproducedinlargerpatientgroups.
latedwhetherthevariationmightbecausedbyfood,drug
In conclusion, we have demonstrated a significant
intake, or activities that influence release of serotonin.
correlation between paired 24-h and overnight/8-h
Basedontheirobservations,theysuggestedthatovernight
U5-HIAA samples. Thus, overnight U5-HIAA measure-
urinecollectioncouldreplace24-hcollectionforU5-HIAA
ment may replace the more cumbersome 24-h collection
analyses(6).Inanearlierstudy,Kemaetal.(17)foundno
in follow-up of patients with intestinal NETs. As our
consistent variations for 5-HIAA in two consecutive 12-h
urine samples compared with 24-h samples from 15 cohort had already been diagnosed with NETs, the
healthy adults, which also indicates that a collection accuracyofovernight5-HIAAmeasurementfordiagnosis
intervalof!24hmightbesufficienttogivearepresenta- of NETs in an unselected population will need further
tivepictureofserotoninlevels. studies.Moreover,ourstudywasperformed inahospital
Still, current guidelines from European Neuroendo- environment and may therefore not be generalizable to
crineTumorSociety(18)hold24-hsamplingofU5-HIAA outpatientcollections.
as the standard, and in 2009, they also suggest two
consecutive 24-h collections for diagnostic purposes (8).
North American Neuroendocrine Tumor Society’s con- Declarationofinterest
sensusguidelinesforthediagnosisofNETs2010statethat The authors declare that there is no conflict of interest that could be
perceivedasprejudicingtheimpartialityoftheresearchreported.
24-hU5-HIAAcollectionisthemostusefulmeasurement
formonitoringNETsoriginatingfromtheintestine(19).
Acidification of the 24-h urine collection sample
Funding
has been a necessity because of the long storage time.
Thisresearchdid notreceiveanyspecificgrant fromany agency inthe
The shorter storage interval required when applying public,commercial,ornot-for-profitsector.
http://www.endocrineconnections.org (cid:1)2013TheAuthors.PublishedbyBioScientificaLtd.ThisisanOpenAccessarticle
DOI:10.1530/EC-12-0077 distributedunderthetermsoftheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedthe
originalauthorandsourcearecredited.
Research MGedde-Dahletal. 24-hvs.w8-hurinary5-HIAA 5–5 2:54
neuroendocrinecarcinomasofthegastroenteropancreatictract.British
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withthestatisticalanalyses. WymengaAN&DeVriesEG.Persistentlowurinaryexcretionof
5-HIAAisamarkerforfavourablesurvivalduringfollow-upinpatients
withdisseminatedmidgutcarcinoidtumours.EuropeanJournalof
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Accepted14December2012
http://www.endocrineconnections.org (cid:1)2013TheAuthors.PublishedbyBioScientificaLtd.ThisisanOpenAccessarticle
DOI:10.1530/EC-12-0077 distributedunderthetermsoftheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedthe
originalauthorandsourcearecredited.