Abstract
OBJECTIVE:
The objective of this trial was to determine the levels of inflammatory markers, high-sensitivity C-reactive protein and fetuin-A pre- and post-levothyroxine treatment in cases of subclinical hypothyroidism.
MATERIALS AND METHODS:
A total of 32 patients with a diagnosis of subclinical hypothyroidism and a control group of 30 healthy individuals were tested for high-sensitivity C-reactive protein and fetuin-A, followed by the administration of 50 µg of levothyroxine in the patient group for 3 months. During the post-treatment stage, high-sensitivity C-reactive protein and fetuin-A levels in the patient group were re-assessed and compared with pre-treatment values.
RESULTS:
Pre-treatment levels of both high-sensitivity C-reactive protein and fetuin-A were observed to be higher in the patient group than in the control group. The decrease in high-sensitivity C-reactive protein levels during the post-treatment stage was not statistically significant. However, the decrease observed in post-treatment fetuin-A levels was found to be statistically significant.
CONCLUSION:
The decrease in fetuin-A levels in subclinical hypothyroidism cases indicates that levothyroxine treatment exerts anti-inflammatory and anti-apoptotic effects. Although the decrease in high-sensitivity C-reactive protein levels was statistically non-significant, it is predicted to reach significance with sustained treatment.
Subclinical Hypothyroidism; hs-CRP; Fetuin-A; Levothyroxine
INTRODUCTION
Subclinical hypothyroidism (SHO) is a common thyroid disorder and its prevalence in
the adult population has been reported to be 1-10%. Furthermore, SHO has been found
to be more common in the elderly population (11 Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in
the elderly. Microsomal antibodies as discriminant for therapy. JAMA.
1987;258(2):209-13.,22 Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F,
et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin
Endocrinol (Oxf). 1977;7(6):481-93,
http://dx.doi.org/10.1111/j.1365-2265.1977.tb01340.x.
http://dx.doi.org/10.1111/j.1365-2265.19...
). The diagnosis of SHO is
based on a high serum thyroid-stimulating hormone (TSH) level and a normal free
thyroxin level. SHO is asymptomatic in general; however, symptoms suggestive of
thyroid hormone deficiency may be present in 30% of patients (33 Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG, et
al. American Thyroid Association guidelines for detection of thyroid
dysfunction. Arch Intern Med. 2000;160(11):1573-5,
http://dx.doi.org/10.1001/archinte.160.11.1573.
http://dx.doi.org/10.1001/archinte.160.1...
4 McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild
thyroid failure and should be treated. J Clin Endocrinol Metab.
2001;86(10):4585-90, http://dx.doi.org/10.1210/jcem.86.10.7959.
http://dx.doi.org/10.1210/jcem.86.10.795...
-55 Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado
thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526-34,
http://dx.doi.org/10.1001/archinte.160.4.526.
http://dx.doi.org/10.1001/archinte.160.4...
). In a
cross-sectional study of 2336 cases of SHO, the symptoms identified were as follows
dry skin in 28% of patients, dysmnesia in 24%, deficiency of judgment in 22%, muscle
weakness in 22%, malaise in 18%, muscle cramps in 17%, cold intolerance in 15%,
swelling in eyelids in 12%, constipation in 8% and hoarseness in 7% (5). These
symptoms were found in 13.7% of the SHO group, in 12.1% of the euthyroid group and
in 16.6% of the hypothyroidism group, revealing a statistically significant
difference. This finding also showed a correlation between symptoms and thyroid
hormone levels in 16.6% of the hypothyroidism group. Diverse symptoms of varying
severity levels may develop in cases of SHO, although the disease is theoretically
regarded as asymptomatic. In any case, the presence of similar symptoms in euthyroid
groups and the lack of detailed, large-scale trials on the treatment response
related to this topic have led to the emergence of diverse treatment approaches.
Depression, amnesia, deficiency in cognitive functions and various neuromuscular
complaints and disorders have been reported in patients with SHO (66 Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini
E. Clinical and biochemical features of muscle dysfunction in subclinical
hypothyroidism. J Clin Endocrinol Metab. 1997;82(10):3315-8,
http://dx.doi.org/10.1210/jcem.82.10.4296.
http://dx.doi.org/10.1210/jcem.82.10.429...
7 Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E.
Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients:
beneficial effect of L-T4 replacement therapy. Clin Endocrinol (Oxf).
1999;51(2):237-42,
http://dx.doi.org/10.1046/j.1365-2265.1999.00790.x.
http://dx.doi.org/10.1046/j.1365-2265.19...
8 Misiunas A, Niepomniszcze H, Ravera B, Faraj G, Faure E.
Peripheral neuropathy in subclinical hypothyroidism. Thyroid. 1995;5(4):283-6,
http://dx.doi.org/10.1089/thy.1995.5.283.
http://dx.doi.org/10.1089/thy.1995.5.283...
-99 Beyer IW, Karmali R, Demeester-Mirkine N, Cogan E, Fuss MJ. Serum
creatine kinase levels in overt and subclinical hypothyroidism. Thyroid.
1998;8(11):1029-31, http://dx.doi.org/10.1089/thy.1998.8.1029.
http://dx.doi.org/10.1089/thy.1998.8.102...
). In
addition, abnormal heart function has been shown related to disordered myocardial
contraction and diastolic dysfunction (1010 Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical
hypothyroidism. Thyroid. 2000;10(8):665-79,
http://dx.doi.org/10.1089/10507250050137743.
http://dx.doi.org/10.1089/10507250050137...
11 Arem R, Rokey R, Kiefe C, Escalante DA, Rodriguez A. Cardiac
systolic and diastolic function at rest and exercise in subclinical
hypothyroidism: effect of thyroid hormone therapy. Thyroid. 1996;6(5):397-402,
http://dx.doi.org/10.1089/thy.1996.6.397.
http://dx.doi.org/10.1089/thy.1996.6.397...
12 Bell GM, Todd WT, Forfar JC, Martyn C, Wathen CG, Gow S, et al.
End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin
Endocrinol (Oxf). 1985;22(1):83-9,
http://dx.doi.org/10.1111/j.1365-2265.1985.tb01068.x.
http://dx.doi.org/10.1111/j.1365-2265.19...
13 Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti
C, et al. Effect of levothyroxine on cardiac function and structure in
subclinical hypothyroidism: a double blind, placebo-controlled study.
J Clin Endocrinol Metab. 2001;86(3):1110-5,
http://dx.doi.org/10.1210/jcem.86.3.7291.
http://dx.doi.org/10.1210/jcem.86.3.7291...
-1414 Ridker PM. High-sensitivity C-reactive protein: potential
adjunct for global risk assessment in the primary prevention of cardiovascular
disease. Circulation. 2001;103(13):1813-8,
http://dx.doi.org/10.1161/01.CIR.103.13.1813.
http://dx.doi.org/10.1161/01.CIR.103.13....
).
Fetuin-A (α-Heremans-Schmid glycoprotein) is a circulating glycoprotein
secreted by the liver into the circulation. Links between fetuin-A and
cardiovascular disease, insulin resistance, diabetes mellitus, metabolic syndrome
and non-alcoholic fatty liver have been reported (1515 Kahraman A, Sowa J-P, Schlattjan M, Sydor S, Pronadl M, Wree A,
et al. Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients.
Clin Sci (Lond). 2013;125(8):391-400,
http://dx.doi.org/10.1042/CS20120542.
http://dx.doi.org/10.1042/CS20120542...
16 Ix JH, Shlipak MG, Brandenburg VM, Ali S, Ketteler M, Whooley
MA. Association between human fetuin-A and the metabolic syndrome: data from the
Heart and Soul Study. Circulation. 2006;113(14):1760-7,
http://dx.doi.org/10.1161/CIRCULATIONAHA.105.588723.
http://dx.doi.org/10.1161/CIRCULATIONAHA...
17 Mori K, Emoto M, Yokoyama H, Araki T, Teramura M, Koyama H, et
al. Association of serum fetuin-A with insulin resistance in type 2 diabetic and
nondiabetic subjects. Diabetes Care. 2006;29(2):468,
http://dx.doi.org/10.2337/diacare.29.02.06.dc05-1484.
http://dx.doi.org/10.2337/diacare.29.02....
18 Stefan N, Fritsche A, Weikert C, Boeing H, Joost H-G,
Häring H-U, et al. Plasma fetuin-A levels and the risk of type 2 diabetes.
Diabetes. 2008;57(10):2762-7,
http://dx.doi.org/10.2337/db08-0538.
http://dx.doi.org/10.2337/db08-0538...
-1919 Bilgir O, Bilgir F, Topcuoglu T, Calan M, Calan O. Comparison of
high-sensitivity C-reactive protein and fetuin-A levels before and after
treatment for subjects with subclinical hyperthyroidism.
Endocrine.2014;45(2):244-8,
http://dx.doi.org/10.1007/s12020-013-9993-z.
http://dx.doi.org/10.1007/s12020-013-999...
).
Our trial was planned to investigate the levels of the subclinical inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and the anti-inflammatory, anti-apoptotic protein fetuin-A in SHO cases and in a healthy control group. In addition, the study aimed to show possible alterations in these inflammatory and anti-inflammatory markers following levothyroxine treatment in patients with SHO.
MATERIALS AND METHODS
A total of 32 patients referred to the Outpatient Clinic of the Department of Internal Diseases at İzmir Bozyaka Education and Research Hospital for any reason from 2009-2011 were enrolled in this trial. The selected patients had TSH levels over 5 mIU/mL and normal FT3 and FT4 levels during routine laboratory examinations and a diagnosis of SHO. The exclusion criteria were the administration of treatment for any condition, surgery on the thyroid or radioactive iodine treatment and a history of chronic disease; accordingly, the cases not meeting the designated criteria were enrolled. In addition, 30 healthy individuals were enrolled on a voluntary basis to generate a healthy control group. Patients with SHO were treated with levothyroxine at 50 µg/day for 3 months, as appropriate based on the indication and venous blood samples were also collected during the post-treatment stage. The trial was initiated upon approval of the study protocol by the Ethical Committee of İzmir Bozyaka Education and Research Hospital.
To determine TSH, FT3, FT4, hs-CRP and fetuin-A levels, 10-mL venous blood samples were obtained from the SHO cases and healthy controls during the pre- and post-treatment stages and placed in non-anticoagulant tubes. The blood samples were kept at room temperature for approximately 30 minutes until the blood was coagulated and then centrifuged at 4000 RPM for 5 minutes. Serum TSH, FT3 and FT4 levels were assessed using the chemiluminescence immunoassay method (Immulite 2000 XPi, Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA).
To determine hs-CRP and fetuin-A levels, the serum samples were placed in Eppendorf tubes and kept frozen at -80°C. Following the collection of all samples, the serum samples were thawed and hs-CRP (DRG Instruments GmbH, Marburg, Germany) and fetuin-A (BioVendor, Modrice, Czech Republic) levels were determined using the enzyme-linked immunosorbent assay (ELISA) method according to the manufacturers' protocols.
Statistical analysis
All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS; version 11.0 for Windows, Chicago, IL, USA). The data are expressed as the mean ± standard deviation (SD). A two-sided p-value<0.05 was considered statistically significant.
A nonparametric Mann-Whitney U test was used to compare the variables between patients and controls and the Wilcoxon signed-rank test was used to compare the variables between treated and untreated SHO patients.
RESULTS
The pre- and post-treatment FT3, FT4, TSH, hs-CRP and fetuin-A levels of the patients with SHO and the healthy control group are shown in Table 1. The mean ages of the 32 SHO cases and the 30 healthy controls were determined to be similar.
There was a significant difference in hs-CRP, fetuin-A, FT3 and TSH levels between pretreatment of SHO group and control group (Figures 1, 2 and 3). After treatment, fetuin-A levels were significantly decreased in the SHO patients. However, no statistically significant difference was observed in hs-CRP levels with treatment. The decrease observed in hs-CRP levels during the post-treatment stage was not statistically significant (Figure 1). In contrast, the decrease observed in post-treatment fetuin-A levels was found to be statistically significant (Figure 2). Comparison of pre- and post-treatment TSH values revealed a significant decrease in post-treatment TSH levels (Figure 3). Comparison of pre- and post-treatment FT3 and FT4 values did not reveal a significant difference.
Comparisons of hs-CRP level in SHO group, SHO patients after treatment and healthy controls. (*p<0.001) (**p = 0.440)Abbreviation: SHO, subclinical hypothyroidism.
Comparisons of fetuin A level in SHO group, SHO patients after treatment and healthy controls. (*p = 0.019) (**p = 0.012)Abbreviation: SHO, subclinical hypothyroidism.
- Comparison of pre-treatment and post-treatment TSH, FT3 and FT4 values of patients with Subclinical Hypothyroidism and healthy control group.Abbreviation: SHO, subclinical hypothyroidism.
DISCUSSION
SHO is a common disease affecting 3 million individuals in the United Kingdom and 15 million individuals in the USA. The importance of this disease is based on data indicating its potential to induce an atherogenic lipid profile and endothelial dysfunction. In addition, co-morbidity of SHO and cardiovascular disease and an increase in mortality rates have been reported in several studies. Considering the serious outcomes of such a common disease, the importance of trials that have been and will be performed is increasing.
The acute-phase reactant hs-CRP is known to be an exceptionally sensitive and
non-specific marker for inflammation, tissue damage and infection. Elevated hs-CRP
levels indicate the presence and severity of inflammation (1414 Ridker PM. High-sensitivity C-reactive protein: potential
adjunct for global risk assessment in the primary prevention of cardiovascular
disease. Circulation. 2001;103(13):1813-8,
http://dx.doi.org/10.1161/01.CIR.103.13.1813.
http://dx.doi.org/10.1161/01.CIR.103.13....
). In current clinical practice, serum hs-CRP measurements
are used to determine risks and to monitor treatment effectiveness. Hs-CRP is a
cardiovascular risk marker, which has been regarded as significant in recent years
following the recognition of atherosclerosis as an inflammatory disease. The
correlation of SHO and prominent hypothyroidism with coronary heart disease in
particular has been shown in a number of trials. However, although hypothyroidism
and atherosclerosis are closely related, the correlation between thyroid function
tests and hs-CRP levels has varied among different trials.
Currently, hs-CRP is regarded as a predictive marker for myocardial infarction,
stroke, peripheral artery disease and sudden cardiac death among individuals with no
cardiovascular disease and as a predictive marker for recurrent attacks and
mortality in cases of metabolic syndrome (2020 Bassuk SS, Rifai N, Ridker PM. High-sensitivity C-reactive
protein: clinical importance. Curr Probl Cardiol.
2004;29(8):439-93.). Based on previous trials, in terms of cardiovascular risk, individuals
with hs-CRP levels <1 mg/L are regarded as low risk; individuals with levels
between 1-3 mg/L, as moderate risk; and individuals with levels>3 mg/L, as high
risk (2121 Ridker PM, Cook N. Clinical usefulness of very high and very low
levels of C-reactive protein across the full range of Framingham Risk Scores.
Circulation. 2004;109(16):1955-9,
http://dx.doi.org/10.1161/01.CIR.0000125690.80303.A8.
http://dx.doi.org/10.1161/01.CIR.0000125...
). Recent data suggest that CRP has a
direct role in atherogenesis. CRP induces the expression of intracellular adhesion
molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in endothelial cells
and mediates monocyte chemoattractant protein (MCP-1) induction and the phagocytosis
of LDL by macrophages. CRP induces the synthesis of tissue factor, a strongly
pro-coagulant substance, in monocytes and may bind to activated complement (2222 Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular
risk prediction. J Intern Med. 2002;252(4):283-94,
http://dx.doi.org/10.1046/j.1365-2796.2002.01019.x.
http://dx.doi.org/10.1046/j.1365-2796.20...
). As a result of all of these actions, CRP
plays a role in endothelial dysfunction (2323 Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S,
Zeiher AM. Elevated C-reactive protein levels and impaired endothelial
vasoreactivity in patients with coronary artery disease. Circulation.
2000;102(9):1000-6,
http://dx.doi.org/10.1161/01.CIR.102.9.1000.
http://dx.doi.org/10.1161/01.CIR.102.9.1...
).
In many trials conducted in diverse groups, a strong correlation was found between
CRP levels and cardiovascular disease (2424 Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. Elevated
C-reactive protein levels and increased cardiovascular risk in patients with
obstructive sleep apnea syndrome. Int Heart J. 2005;46(5):801-9,
http://dx.doi.org/10.1536/ihj.46.801.
http://dx.doi.org/10.1536/ihj.46.801...
).
In one trial performed in a patient group with a history of myocardial infarction,
stroke and venous thrombosis and in a control group with no history of the indicated
diseases, the patients were followed for 14 years and a group with trough hs-CRP
values (<0.55 mg/L) was compared with a group with maximum values (>2.11
mg/L). The results indicated a 2-fold increase in stroke risk, a 3-fold increase in
myocardial infarction and a 4-fold increase in symptomatic peripheral vascular
disease in the group with maximum values (2525 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.
Plasma concentration of C-reactive protein and risk of developing peripheral
vascular disease. Circulation. 1998;97(5):425-8,
http://dx.doi.org/10.1161/01.CIR.97.5.425.
http://dx.doi.org/10.1161/01.CIR.97.5.42...
). The role of hs-CRP in coronary heart disease was shown in another
trial. Basal hs-CRP concentrations were measured in a healthy middle-aged group that
was then followed for 8 years and an increase in the SD of hs-CRP levels was shown
to increase the risk of coronary heart disease by 50% (2626 Koenig W, Sund M, Fröhlich M, Fischer HG, Löwel H,
Döring A, et al. C-Reactive protein, a sensitive marker of inflammation,
predicts future risk of coronary heart disease in initially healthy middle-aged
men: results from the MONICA (Monitoring Trends and Determinants in
Cardiovascular Disease) Augsburg Cohort Study, 1984. Circulation.
1999;99(2):237-42, http://dx.doi.org/10.1161/01.CIR.99.2.237.
http://dx.doi.org/10.1161/01.CIR.99.2.23...
).
In the current trial, levothyroxine was administered in cases of SHO for 3 months and differences in hs-CRP values following treatment (if any) were assessed. Although a decrease was observed in these values, it did not reach a statistically significant level (p = 0.440). However, statistically significant decreases may be obtained by increasing the dose of levothyroxine used in treatment, which is expected to further decrease TSH values and by prolonging the treatment duration.
Fetuin-A is a protein with anti-inflammatory and anti-apoptotic effects. Mice with
fetuin gene ablation are congenitally prone to calcifications, leading to fatal
calcifications in the kidneys, testes, skin, heart and vessels (2727 Jahnen-Dechent W, Schinke T, Trindl A, Müller-Esterl W,
Sablitzky F, Kaiser S, et al. Cloning and targeted deletion of the mouse fetuin
gene. J Biol Chem. 1997;272(50):31496-503,
http://dx.doi.org/10.1074/jbc.272.50.31496.
http://dx.doi.org/10.1074/jbc.272.50.314...
). Fetuin-A may inhibit the activity of the
insulin receptor tyrosine kinase, which causes insulin resistance. This glycoprotein
also regulates bone development and re-formation by antagonizing the activity of
TGF-β (2828 Szweras M, Liu D, Partridge EA, Pawling J, Sukhu B, Clokie C, et
al. alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone
morphogenetic protein antagonist, regulates postnatal bone growth and
remodeling. J Biol Chem. 2002;277(22):19991-7,
http://dx.doi.org/10.1074/jbc.M112234200.
http://dx.doi.org/10.1074/jbc.M112234200...
). The normal serum
concentration is 0.5-1 g/L and the levels decrease during inflammation. In addition,
an inverse correlation has been reported between serum fetuin-A and CRP (2929 Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH,
Böhm R, et al. Association of low fetuin-A (AHSG) concentrations in serum
with cardiovascular mortality in patients on dialysis: a cross-sectional study.
Lancet. 2003;361(9360):827-33,
http://dx.doi.org/10.1016/S0140-6736(03)12710-9.
http://dx.doi.org/10.1016/S0140-6736(03)...
). Low fetuin-A levels among hemodialysis
patients are associated with a high risk of cardiovascular disease and increased
mortality. The main activity of fetuin-A is the inhibition of Ca-P accumulation.
In vitro, this protein has been shown to inhibit the formation
of apatites in osteoblast cultures. In addition, fetuin-A displays anti-inflammatory
activity by regulating the phagocytosis of apoptotic particles by macrophages (3030 Heiss A, DuChesne A, Denecke B, Grötzinger J, Yamamoto K,
Renné T, et al. Structural basis of calcification inhibition by alpha 2-HS
glycoprotein/fetuin-A. Formation of colloidal calciprotein
particles. J Biol Chem. 2003;278(15):13333-41.,3131 Jersmann HPA, Dransfield I, Hart SP. Fetuin/alpha2-HS
glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by
human macrophages. Clin Sci (Lond). 2003;105(3):273-8,
http://dx.doi.org/10.1042/CS20030126.
http://dx.doi.org/10.1042/CS20030126...
).
In one trial, fetuin-A was reported to play a role in the inhibition of
calcification in vascular smooth muscle cells (3232 Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg
PL, et al. Multifunctional roles for serum protein fetuin-a in inhibition of
human vascular smooth muscle cell calcification. J Am Soc Nephrol.
2005;16(10):2920-30, http://dx.doi.org/10.1681/ASN.2004100895.
http://dx.doi.org/10.1681/ASN.2004100895...
).
In a trial conducted in adults, a comparison of the fetuin-A levels of healthy
controls and a patient group comprising end-stage renal failure and dialysis cases
revealed significantly low levels in both groups (3333 Kuźniar J, Porazko T, Klinger M. Relationship between
fetuin-A concentration, elevated levels of inflammatory markers, and arterial
wall stiffness in end-stage kidney disease. J Ren Nutr.
2008;18(1):83-6.). In another trial conducted in 141 healthy individuals, serum
fetuin-A levels and sclerosis of the vessel wall in the carotid artery were shown to
be correlated and this correlation was indicated to be significant and independent
of other well-known atherogenic factors (3434 Mori K, Emoto M, Araki T, Yokoyama H, Teramura M, Lee E, et al.
Association of serum fetuin-A with carotid arterial stiffness. Clin Endocrinol
(Oxf). 2007;66(2):246-50,
http://dx.doi.org/10.1111/j.1365-2265.2006.02716.x.
http://dx.doi.org/10.1111/j.1365-2265.20...
).
Accordingly, in the present study, a statistically significant decrease was found in fetuin-A levels following 3 months of levothyroxine treatment compared with pre-treated values in cases of SHO. Considering that the etiology of the majority of SHO cases is thyroiditis, it is evident that even short-term levothyroxine treatment exerts anti-inflammatory and anti-apoptotic effects in these patients. Hence, even in cases without any alterations in FT3 and FT4 levels, thyroid replacement treatment may decrease the need for the management of future cardiovascular problems that would otherwise be expected to develop based on endothelial dysfunction and an atherogenic lipid profile.
ACKNOWLEDGMENTS
All of the subjects who contributed to the fulfillment of this work are duly acknowledged.
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» http://dx.doi.org/10.1111/j.1365-2265.1977.tb01340.x -
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» http://dx.doi.org/10.1210/jcem.86.10.7959 -
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» http://dx.doi.org/10.1001/archinte.160.4.526 -
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» http://dx.doi.org/10.1210/jcem.82.10.4296 -
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» http://dx.doi.org/10.1046/j.1365-2265.1999.00790.x -
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» http://dx.doi.org/10.1089/thy.1995.5.283 -
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» http://dx.doi.org/10.1089/thy.1998.8.1029 -
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» http://dx.doi.org/10.1089/10507250050137743 -
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Feb 2015
History
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Received
8 Sept 2014 -
Reviewed
14 Oct 2014 -
Accepted
5 Dec 2014