Fetuin-A levels in hyperthyroidism.

0.38 MB·English

by  Pamuk, Bar?s Onder

CLINICAL SCIENCE
Fetuin-A levels in hyperthyroidism
Barıs¸ Onder Pamuk,I Hamiyet Yılmaz,I Tugba Topcuoglu,II Oktay Bilgir,II Ozlem C¸alan,III Gulseren Pamuk,IV
Derun Taner ErtugrulV
IIzmirBozyakaTeachingandResearchHospital,DepartmentofEndocrinologyandMetabolism,Izmir,Turkey.IIIzmirBozyakaTeachingandResearch
Hospital,DepartmentofInternalMedicine,Bozyaka,Izmir.IIIIzmirBozyakaTeachingandResearchHospital,DepartmentofBiochemistry,Bozyaka,Izmir,
Turkey. IVIzmir Bozyaka Teaching and Research Hospital, Department of Family Medicine,Bozyaka, Izmir, Turkey. VKecioren Teaching and Research
Hospital,DepartmentofEndocrinologyandMetabolism,Ankara,Turkey.
OBJECTIVE: Fetuin-A is a protein secreted from the liver that inhibits arterial calcification deposition and can
contribute to insulin resistance. Hyperthyroidism is also associated with insulin resistance. It is not known
whetherhyperthyroidism hasaneffect onfetuin-A levels.
METHODS: We measured fetuin-A levels and homeostasis model of assessment-insulin resistance before
hyperthyroidismtreatmentwasinitiatedandaftereuthyroidismwasachieved.Atotalof42patientsdiagnosed
with hyperthyroidism were enrolled in this study. Fetuin-A, insulin, high-sensitivity C-reactive protein, fasting
bloodglucose,freeT3(fT3),freeT4(fT4),andthyrotropinweremeasuredbeforeandaftereuthyroidismwas
established.
RESULTS:Basalfastingbloodglucose,high-sensitivityC-reactiveprotein,insulin,c-peptide,homeostasismodel
of assessment-insulin resistance, fT3, fT4 and fetuin-A levels were significantly decreased after euthyroidism
wasachieved(Table1).Basalfastingbloodglucose(r:0.407,p:0.008),high-sensitivityC-reactiveprotein(r:0.523,
p,0.0001),insulin(r:0.479,p:0.001),homeostasismodelofassessment-insulinresistance(r:0.541,p,0.0001),fT3
(r:0.492, p:0.001) and fT4 (r:0.473, p:0.002) were positively correlated with basal fetuin-A levels. Basal
thyrotropin levelsweresignificantly negatively correlated (r:-0.553, p,0.0001)withbasal fetuin-A levels.
CONCLUSION:Our findings suggestthathyperthyroidism influences fetuin-A levels.
KEYWORDS: Fetuin-A; Hyperthyroidism; InsulinResistance.
PamukBO,YılmazH,TopcuogluT,BilgirO,C¸alanO,PamukG,etal.Fetuin-Alevelsinhyperthyroidism.Clinics.2013;68(3):379-383.
ReceivedforpublicationonDecember16,2012;FirstreviewcompletedonJanuary8,2013;AcceptedforpublicationJanuary26,2013
E-mail:[e-mail]
Tel.:[phone]
& INTRODUCTION associatedwithhepatosteatosisandareelevatedinpatients
withinsulinresistance(8).Fetuin-Acanalsobevaluablefor
Fetuin-A is a proteinsecreted fromthe liver thatinhibits
thepredictionofnew-onsettype2diabetes.IntheEuropean
arterialcalciumdeposition(1).Itinteractswithcalciumand
Prospective Investigation into Cancer and Nutrition Study,
phosphorus in the serum, increasing their solubility and
circulatingfetuin-Alevelspredictedtheincidenceoftype2
inhibiting calcium crystal precipitation. Fetuin-A-knockout
diabetes during a 7-yr follow-up (9). In the Health, Aging,
mice have been shown to develop greater soft tissue
and Body Composition study, serum fetuin-A levels were
calcification compared with wild-type control mice (2-3).
alsosignificantlyassociatedwithincidentdiabetesduringa
Lower fetuin-A levels are associated with cardiovascular
6-yrfollow-up (10).
disease (CVD) events and all-cause mortality in end-stage
Hyperthyroidismisalsoassociatedwithinsulinresistance
renal disease(ESRD) (4).
andelevatedbloodglucoselevels(11-12).However,thelink
Fetuin-Ainhibitsinsulinreceptortyrosinekinaseactivity
betweenhyperthyroidismandinsulinresistancehasnotbeen
inthemuscleandliver,therebyinhibitinginsulinsignaling
fullyelucidated.Toourknowledge,fetuin-Alevelshavenot
and introducing insulin resistance in vitro (5). In humans,
beenmeasuredinhyperthyroidism.Inthisstudy,weaimed
fetuin-A may be an important link between obesity and
toinvestigatetheleveloffetuin-Ainhyperthyroidism.
insulin resistance (6-7). Fetuin-A concentrations are also
& METHODS
Copyright (cid:2) 2013CLINICS–ThisisanOpenAccessarticledistributedunder A total of 42 patients diagnosed with hyperthyroidism
thetermsoftheCreativeCommonsAttributionNon-CommercialLicense(http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- were enrolled in this study. Blood samples were collected
commercial use, distribution, and reproduction in any medium, provided the before hyperthyroidism treatment was initiated and after
originalworkisproperlycited. euthyroidism was achieved. Serum glucose levels were
Nopotentialconflictofinterestwasreported. measured with an autoanalyzer with the manufacturer’s
DOI:10.6061/clinics/2013(03)OA15 commerciallyavailablekits(Cobas8000,RocheDiagnostics,
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Hyperthyroidismandfetuin-A CLINICS2013;68(3):379-383
PamukBOetal.
Table 1-Biochemical resultsbefore andafter euthyroidismwas achieved(mean¡SD).
Parameter(referencevalues) Hyperthyroid Euthyroid p-value
Fetuin-A(ng/mL) 468.7¡143.5 234.5¡103.8 ,0.0001
FT3(pg/mL)(2.5-3.9) 8.6¡2.3 2.7¡0.3 ,0.0001
FT4(ng/dL)(0.61-1.06) 4.7¡1.6 1.2¡0.4 ,0.0001
TSH(mIU/mL)(0.41-4.25) 0.006¡0.014 0.986¡0.467 ,0.0001
Fastingbloodglucose(mg/dL)(70- 113.1¡15.6 94.8¡22.2 ,0.0001
110)
Insulin(mU/mL)(1.9-23) 13.1¡2.5 8.5¡2.1 ,0.0001
HOMA-IR 3.69¡1.07 2.00¡0.67 ,0.0001
hsCRP(mg/L)(0.068-8.2) 6.27¡2.65 1.92¡0.79 ,0.0001
Calcium(mg/dL)(8.6-10.2) 10.1¡0.4 9.4¡0.3 ,0.0001
Mannheim, Germany). Free T3, free T4, TSH and insulin normaldistribution.AWilcoxonsignedranktestwasused
levels were measured with a chemiluminescence immuno- to analyze data with a skewed distribution. Pearson’s and
metric assay using a UniCell DXI 800 analyzer (Beckman Spearman’s analyses were used to identify correlations
CoulterInc.,Fullerton,CA,USA).SerumhsCRPlevelswere between study parameters. For all statistics, a two-sided p-
determinedusinganELISAaccordingtothemanufacturer’s value ,0.05 was considered statistically significant. All
instructions (DRG International, Inc., USA). The intra- and analyses wereperformed with SPSS15.0for Windows.
inter-assaycoefficientsofvariationwerebelow10%.Serum
fetuin-A levels were measured with a human fetuin-A & RESULTS
ELISA kit (BioVendor Laboratory Medicine, Brno, Czech Ofthe42hyperthyroidpatients(48.5¡15.0yearsold),27
Republic). The analytical sensitivity of the human fetuin-A
patientswerefemale,and15weremale.Amongthecauses
ELISA kit was 0.35 ng/mL. The intra- and inter-assay
of hyperthyroidism, 30 patients had Graves’ disease, 11
coefficients of variation were below 6.5%. The exclusion
patients had toxic adenoma, and 1 patient had two toxic
criteria were previously known diabetes mellitus, athero- nodules. Euthyroidism was achieved in 3.0¡0.7
sclerotic vascular disease, infections, malignancy, amyloi- (mean¡SD) months. Basal fasting blood glucose, hsCRP,
dosis, autoimmune diseases, alcohol consumption or insulin, HOMA-IR, fT3, fT4, calcium and fetuin-A levels
smokinghistory,congestiveheartfailure,andliverorrenal were significantly decreased after euthyroidism was
dysfunction. HOMA-IR was calculated using the following achieved (Table 1) (Figure 1). Basal fasting blood glucose
formula: (r:0.407,p:0.008),hsCRP(r:0.523,p,0.0001),insulin(r:0.479,
HOMA-IR=fasting glucose (mmol/L)6fasting insulin p:0.001), HOMA-IR(r:0.541, p,0.0001),fT3 (r:0.492, p:0.001)
(mU/mL)/22.5. and fT4 (r:0.473, p:0.002) were positively correlated with
The distribution of continuous variableswas determined basal fetuin-A levels (Figures 2, 3). Basal TSH levels were
by the Kolmogorov-Smirnov test. A paired-sample t test significantly negatively correlated (r:-0.553, p,0.0001) with
was performed to analyze initial and final values with a basal fetuin-A levels. The basal body mass index (before:
Figure1-Thecomparisonoffetuin-A(ng/mL)levelsduringhyperthyroidismandeuthyroidism.
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CLINICS2013;68(3):379-383 Hyperthyroidismandfetuin-A
PamukBOetal.
Figure2-ThecorrelationbetweenfreeFT4(referencerange:0.61-1.06ng/dL)andfetuin-A(ng/mL)levels.
Figure3-ThecorrelationbetweenTSH(uIU/mL)andfetuin-A(ng/mL)levels.
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Hyperthyroidismandfetuin-A CLINICS2013;68(3):379-383
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27.1¡3.2, after: 28.2¡3.7, p,0.0001) increased significantly (13). In addition to its functions as an inhibitor of tissue
after euthyroidism wasachieved. calcification, fetuin-A is an endogenous inhibitor of the
insulinreceptortyrosinekinase(14),andfetuin-A-knockout
& DISCUSSION mice exhibit increased insulin sensitivity (15). Recent
studies have associated high levels of fetuin-A with an
In this study, we found that fetuin-A levels decreased increased risk of type 2 diabetes incidence (16), insulin
significantly with hyperthyroidism treatment. To our resistance, hepatosteatosis (8) and metabolic syndrome (7).
knowledge, this is the first study investigating the effect of Lietal.previouslyshowedthatfetuin-Aplaysaprotective
hyperthyroidism on fetuin-A levels. In this study, hsCRP role in systemic inflammation by activating high-mobility
levelsalsodecreasedsignificantlywiththenormalizationof
groupbox1(HMGB1)synthesis(20).Hyperthyroidismmay
thyroid hormones. Furthermore, fetuin-A levels were
also initiate an inflammatory cascade and eventually
positively correlated with thyroid hormone, HOMA-IR
stimulate fetuin-A synthesis. Insulin resistance in
and hsCRPlevels.
hyperthyroidismmayalsoberelatedtotheincreasedlevels
Fetuin-A is a liver-derived blood protein that acts as a
of fetuin-A. Yavuz et al. previously showed that levothyr-
potent inhibitor of ectopic mineralization. Monomeric
oxine treatment of goiter patients significantly increased
fetuin-A protein binds to small clusters of calcium and
hsCRP at 16 weeks (21). In accordance with that study,
phosphate. Therefore, fetuin-A is a mineral carrier protein
we found a significant decrease in hsCRP levels with
andasystemicinhibitorofpathologicalmineralizationthat
hyperthyroidism treatment. Fetuin-A also has strong anti-
complements local inhibitors that act in a cell-restricted or
inflammatory properties (13). In our study, fetuin-A levels
tissue-restricted fashion (13). Fetuin-A deficiency is asso-
decreased with hsCRP levels, which mayalsobe related to
ciated with soft tissue calcification in mice and humans.
theinflammation-fetuin-Ainteraction.Inourstudy,insulin
Fetuin-A is a prominent serum glycoprotein as well as a
levelsweresignificantlypositivelycorrelatedwithfetuin-A
major noncollagenous component of mineralized bone in
levels; furthermore, insulin levels and fetuin-A levels were
mammals. In vitro, fetuin-A can inhibit or stimulate
decreased after euthyroidism was achieved. The relation-
osteogenesis, depending on its concentrations (17). Rasul
shipbetweenfetuin-Aandinsulinhasbeenstudiedinboth
etal.previouslyfoundapositivecorrelationbetweenfetuin-
clinicalandexperimentalstudies.Fetuin-Abindstoinsulin
Aandbonealkalinephosphataseintype2diabeticmales.In
females, fetuin-A was significantly negatively associated receptors in adipose and muscular tissue and inhibits
withC-telopeptidelevels(18).However,theresearchersdid insulin receptor tyrosine kinase activity as well as insulin
not measure thyroid hormones in that study. Thyroid receptor autophosphorylation in vivo and in vitro (13).
hormones increase bone turnover markers, and hyperthyr- Fetuin-A has also been suggested to potentially cause
oidismincreasesboneturnover.Fetuin-Amaybeincreased insulin resistance andmetabolic syndrome (13).
in hyperthyroidism through a mechanism related to bone In the present study, fasting glucose levels decreased
metabolism.Fetuin-Ahasbeenstudiedinseveralmetabolic significantly with hyperthyroidism treatment. Fasting glu-
derangements; however, its role has not been studied in cose levels were significantly positively correlated with
hyperthyroidism. Therefore, we could not compare our fetuin-Alevels.Itwaspreviouslyshownthathigherfetuin-
results with previous studies. A concentrations were associated with type 2 diabetes and
Satoetal.examinedtheeffectsofT3ontheexpressionof insulin resistance (24). In another study, fetuin-A levels
calcification-associatedgenesandfoundthataphysiological were significantly correlated with fasting plasma glucose
concentrationofT3increasedthemRNAlevelofmatrixG1a andCRP(25).Thepresentstudyisinaccordancewiththese
protein (MGP), which is a potent inhibitor of vascular findings, as fetuin-A levels decreased significantly as the
calcification invivo(19).Theyalsoshowedthathyperthyr- fastingglucoselevelsandinsulinresistancedecreasedafter
oidism upregulated MGP mRNA 4.5 fold and reduced the hyperthyroidismtreatment.Atherosclerosishasbeenshown
calciumcontentofrataorticsmoothtissueby11%.Fetuin-A tobeenhancedinhypothyroidism(26).Theanti-atherogenic
also inhibits tissue calcification in a similar fashion; there- effectsofthyroidhormonesmayalsoberelatedtofetuin-A.
fore, we hypothesize that there may be an interaction Further clinical and experimental studies investigating the
between fetuin-A synthesis and thyroid hormones because effect of hypothyroidism on fetuin-A levels may reveal its
we found a positive correlation between these two influence on atherosclerosis inhypothyroidism.
parameters. To our knowledge, no experimental study in In conclusion, this study showed that fetuin-A levels
theliteraturehasinvestigatedtheeffectofthyroidhormones declined significantly after hyperthyroidism treatment.
on the mRNA levels of fetuin-A. Hypercalcemia is a well-
Fetuin-Alevelswerealsocorrelatedwiththyroidhormones
known complication of hyperthyroidism, and stimulating
and insulin resistance. Further experimental studies are
fetuin-Asynthesismaybeanadaptationtopreventectopic
needed to elucidate the molecular link between the
tissue calcification in hyperthyroidism. In a previousstudy
hormones regulating tissue calcification and thyroid hor-
of32thyrotoxicteenagegirls,21(66%)showedsomedegree
mones.
ofcalcificationcomparedwith73of600(12%)inthecontrol
group (22). Yamashita et al. previously observed that
fibroblast growth factor (FGF)-23 levels (which are also & AUTHOR CONTRIBUTIONS
related to soft tissue calcification) decreased significantly
PamukBO,ErtugrulDTconceivedanddesignedthestudy,analyzedand
with hyperthyroidism treatment (23). However, they did
interpretedthedata,draftedthearticle,andcriticallyrevisedthearticlefor
not measure fetuin-A levels, and we therefore cannot
importantintellectualcontent.YılmazH,TopcuogluT,BilgirO,CalanO,
compare ourresults with thatstudy. Pamuk G organized data in the tables, assisted the patients during the
Fetuin-Alevels havebeenfound tobehigher indiabetes study, helped in the literature revision, drafted the manuscript, and
and inflammatory diseases, such as ankylosing spondylitis criticallyrevisedthemanuscriptregardingimportantintellectualcontent.
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CLINICS2013;68(3):379-383 Hyperthyroidismandfetuin-A
PamukBOetal.
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