Sage Journals: Discover world-class research

Abstract

Objective

Adhesion molecules are involved in inflammation, atherosclerosis and malignancy. This study measured levels of adhesion molecules before and after levothyroxine therapy in patients with subclinical hypothyroidism (SHO).

Methods

Levels of soluble (s) intracellular adhesion molecule (ICAM)-1, s vascular cell adhesion molecule (sVCAM) VCAM-1 and sE-selectin were analysed in patients diagnosed with SHO, prior to administration of 50 µg/day levothyroxine orally for 3 months. Subsequently, levels of sICAM-1, sVCAM-1 and sE-selectin were reanalysed then compared with the pretreatment levels.

Results

In 30 patients with SHO, levels of sICAM-1 were found to be significantly higher than those in healthy controls, (P = 0.001). Post-treatment sICAM-1 levels were significantly lower than pretreatment levels (P = 0.001). No significant differences were found in sVCAM-1 or sE-selectin levels between healthy controls and patients with SHO before treatment, or between patients with SHO pre- and post-treatment.

Conclusions

Patients with SHO had significantly higher levels of sICAM-1 compared with controls. Levels became normal after treatment with levothyroxine. These findings emphasize the need for levothyroxine therapy in cases of SHO to normalize sICAM-1 levels. Such treatment helps to prevent the future development of atherosclerosis or cancer.

Keywords

Subclinical hypothyroidism levothyroxine sICAM-1 sVCAM-1 sE-selectin

Introduction

Subclinical hypothyroidism (SHO), which is the most frequently seen thyroid dysfunction, encompasses various diagnoses including mild thyroid failure, compensated hypothyroidism, decreased thyroid reserve, early hypothyroidism, latent hypothyroidism, minimal symptomatic hypothyroidism and preclinical hypothyroidism.^1,2 SHO is a common disorder with a prevalence ranging between 1 and 10% among the adult population in developed countries, as reported in two population studies.^3,4 SHO is diagnosed by detection of elevated thyroid stimulating hormone (TSH) levels (above the upper limit of the normal range) but normal serum free-thyroxine levels. Those with clear SHO are either asymptomatic or demonstrate very few clinical manifestations. The presence of thyroid autoantibodies is an important indicator for the development of SHO,⁵ with 20–30% of individuals with higher TSH levels testing seropositive for thyroid antibodies.⁶ Adhesion molecules are related to inflammatory processes including atherosclerosis, and may be linked with low grade inflammation during SHO.

A small amount of intracellular adhesion molecule (ICAM)-1 is expressed in endothelial cells. Stimulation of endothelial cells by mediators such as interleukin (IL)-1, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and lipopolysaccharides (LPS) increases the expression of ICAM.⁷ This increase in expression is seen in cases of acute and chronic inflammation, and in the presence of tumour cells.⁸ As a consequence of such stimulation, ICAM starts to become apparent on the cell surface after 2–4 h and continues to increase to a plateau level after 12–16 h. If cytokines are present at the same time, then ICAM will be expressed for 24–72 h. ICAM-1 molecules are important for the migration of eosinophils, T-lymphocytes and neutrophils,⁹ and function as important signals in interactions between antigen-presenting cells and T-cells. Proteolytic dissociation of the ICAM-1 extracellular part produces its soluble (sICAM-1) form. The plasma level of this form is a direct indicator of the amount of inflammation in disease states.⁸

Stimulation of cytokines such as IL-1, IL-4 and TNF-α produces expression of vascular cell adhesion molecule (VCAM)-1 on the surface of various cells 2–4 h later. IL-4 selectively induces expression of VCAM-1, and enables the accumulation of eosinophils, which is mediated by very late antigen (VLA)-4.¹⁰ VCAM molecules maintain migration and adhesion of leucocytes on endothelial vessel walls. Both ICAM-1and VCAM-1 play vital roles in the processes of immune response and inflammation. VCAM-1 binds to its ligand VLA-4, and is found in all types of leucocytes excluding neutrophils. The VCAM-1/VLA-4 pathway plays a key role in the pathogenesis of various allergic, inflammatory and autoimmune diseases.¹⁰

In common with VCAM, E-selectin is not found on nonstimulated endothelial cells. E-selectin expression increases in response to inflammatory stimulants such as IL-1, TNF-α or endotoxins (e.g. LPS).³ It appears on the surface of endothelial cells within 30 min of stimulation, and levels peak after 2–4 h. Structurally, the first extracellular domain of E-selectin contains lectin, while the second domain comprises an EGF-like domain. It also contains six additional cysteine-rich protein domains.⁵ Antibodies directly effective on E-selectin prevent inflammation.¹¹ The E-selectin receptor ensures selective binding of neutrophils, monocytes and eosinophils to the endothelium.

The aim of the present study was to determine the levels of adhesion molecules that are thought to have a role in the development of morbidities (such as inflammation, malignancy, allergy and autoimmune disease) in patients with SHO before levothyroxine therapy, and assess if any changes occurred in adhesion molecule levels after 3 months’ levothyroxine treatment.

Patients and methods

Patients

Patients attending the endocrinology outpatients’ clinic at Izmir Bozyaka Training and Research Hospital, Bozyaka, Izmir, Turkey, between September 2009 and April 2011 and diagnosed with SHO during tests for investigation of fatigue or weight gain were enrolled into this study. Criteria for patients to be included in the study were thyroid dysfunction as indicated by laboratory tests; age 27–60 years; thyroid-treatment naïve; no history of thyroid surgery or radioactive iodine therapy.

Detailed medical histories were obtained and physical examinations were performed on patients meeting the study criteria. In addition, healthy volunteers (selected from healthcare workers from Izmir Bozyaka Research and Training Hospital and age and sex matched to patients) were included as a control group. Whole blood count, biochemistry, thyroid function tests and levels of anti-T, anti-M, sE-selectin, sVCAM-1 and sICAM-1 values were measured.

Ethical consent for the study was received from the Izmir Bozyaka Research and Training Hospital Ethics Committee (reference number 358), Bozyaka, Turkey and written informed consent was obtained from all participants.

Blood measurements

Whole-blood cell counts were made using 2-ml venous blood samples drawn into ethylenediaminetetra-acetic acid tubes, and analysed in a CELL-DYN 3700 device (Abbott Laboratories, Abbott Park, IL, USA). Blood samples collected for evaluation of thyroid function were drawn into anticoagulant-free tubes and incubated at room temperature for 30 min until coagulated. Samples were centrifuged at 3220 g for 5 min at room temperature; the separated serum was analysed in an Immulite® 2000 device (Siemens, Erlangen, Germany) using chemiluminencence immunochemistry methods to measure levels of TSH, free thyroxine (FT)3 and FT4. Reference normal laboratory ranges for these parameters were: FT3, 2.5–3.9 pg/ml; FT4, 0.61–1.06 ng/dl; TSH, 0.41–4.25 IU/ml.

The remaining separated serum from each sample was frozen at −80℃ and later used for analysis of E-selectin, sICAM-1 and sVCAM-1 with Biosource (Bender MedSystems GmbH, Vienna, Austria) E-selectin, sICAM-1 and sVCAM-1 kits. No blinding of samples was undertaken during laboratory assessment.

Treatment

Patients were prescribed 50 µg/day levothyroxine, orally, for 3 months after which time blood tests were repeated. Levothyroxine was administered to each patient at a constant dose for a fixed period of time to standardize treatment.

Statistical analyses

Statistical analyses were performed using SPSS® version18.0 (SPSS Inc., Chicago, IL, USA). Differences between levels of E-selectin, sICAM-1 and sVCAM-1 were compared in those with SHO before and after 3 months’ treatment with levothyroxine and in untreated controls, using a nonparametric Wilcoxon’s rank sum test. A P-value < 0.05 was considered statistically significant.

Results

A total of 30 patients diagnosed with SHO (25 female; five male), were included in this study. All patients had Hashimoto’s thyroiditis. The mean age of all patients was 44.28 ± 10.13 years. There were no significant differences in age or sex among the control and SHO groups. Among patients with higher TSH (>4.25 IU/ml) values, those with normal FT3 and FT4 values were considered to have SHO, based on normal laboratory reference ranges. Control, pre- and postlevothyroxine treatment mean values for FT3, FT4, TSH, E-selectin, ICAM-1 and sVCAM-1 are shown in Table 1.

Table 1.

Levels of soluble (s) E-selectin, vascular cell adhesion molecule (sVCAM) and intracellular adhesion molecule (sICAM)-1 in patients with subclinical hypothyroidism (SHO) before and after daily treatment with 50 µg/day levothyroxine, orally, for 3 months compared with healthy controls.

Variable	Control group, n = 30	SHO pretreatment n = 30	SHO post-treatment n = 30	Statistical significance Control group versus SHO pretreatment	Statistical significance SHO pretreatment versus SHO post-treatment
Age, years	43.18 ± 8.45	44.28 ± 10.13	–	P = 0.875	–
Sex, F/M	25/5	25/5	–	P = 1.000	–
TSH, IU/ml	2.14 ± 0.08	65.76 ± 26.85	4.64 ± 2.99	P < 0.001	P = 0.004
FT4, pg/ml	0.89 ± 0.11	0.82 ± 0.13	0.83 ± 0.17	P = 0.432	P = 0.924
FT3, pg/ml	3.28 ± 0.15	3.02 ± 0.43	2.84 ± 0.45	P = 0.108	P = 0.116
sICAM-1, ng/ml	205.42 ± 57.07	552.02 ± 124.52	360.54 ± 128.18	P = 0.001	P = 0.001
sVCAM-1, ng/ml	766.10 ± 812.01	974.96 ± 671.71	1281.77 ± 993.57	P = 0.267	P = 0.294
sE-selectin, ng/ml	70.08 ± 28.96	65.76 ± 26.85	72.07 ± 40.02	P = 0.538	P = 0.158

TSH, thyroid stimulating hormone; FT, free thyroxine.

P < 0.05 was considered statistically significant; nonparametric Wilcoxon’s rank sum.

After 3 months’ levothyroxine therapy, all 30 patients were available for evaluation; all had become euthyroid. A significant drop in mean post-treatment TSH levels was found in patients with SHO compared with mean pretreatment values (P = 0.004). However, no significant difference was observed between pre-and post-treatment FT3 (P = 0.116) and FT4 levels (P = 0.927) in patients with SHO.

Mean sE-selectin, sICAM-1 and sVCAM-1 values are presented in Table 1. Pretreatment sICAM-1 levels were significantly higher in patients with SHO compared with healthy controls (P = 0.001), whereas post-treatment sICAM-I levels were significantly reduced compared with pretreatment values (P = 0.001; Table 1, Figure 1).

Figure 1.

Mean soluble intracellular adhesion molecule (sICAM)-1 levels in patients with subclinical hypothyroidism (SHO) before and after daily treatment with 50 µg/day levothyroxine, orally, for 3 months compared with healthy controls. (a) Mean sICAM-1 levels were significantly higher in pretreatment patients with SHO than in healthy controls (P = 0.001); (b) Mean sICAM-1 levels were significantly lower in post-treatment patients with SHO than in pretreatment patients with SHO (P = 0.001) (nonparametric Wilcoxon’s rank sum test).

There was no significant difference in sVCAM-1 levels between healthy controls and the pretreatment SHO group, or between pre- and post-treatment sVCAM-1 levels in SHO patients (Table 1, Figure 2).

Figure 2.

Mean soluble vascular cell adhesion molecule (sVCAM) levels in patients with subclinical hypothyroidism (SHO) before and after daily treatment with 50 µg/day levothyroxine, orally, for 3 months compared with controls. (a) No significant difference was detected in mean sVCAM-1 levels between pretreatment patients with SHO and healthy controls (P = 0.267); (b) No significant difference was detected in mean sVCAM-1 levels between pre-and post-treatment patients with SHO (P = 0.294) (nonparametric Wilcoxon’s rank sum test).

No significant difference was found between pre-and post-treatment sE-selectin levels in patients, or in levels between healthy controls and pretreatment SHO patients (Table 1, Figure 3).

Figure 3.

Mean sE-selectin levels in patients with subclinical hypothyroidism (SHO) before and after daily treatment with 50 µg/day levothyroxine for 3 months compared with controls. (a) No significant difference was detected in mean sE-selectin levels between pretreatment patients with SHO and healthy controls (P = 0.538); (b) No significant difference was detected in mean sE-selectin levels between pre-and post-treatment patients with SHO (P = 0.158) (nonparametric Wilcoxon’s rank sum test).

Discussion

Thyroid disease, which is becoming increasingly prevalent, both globally and locally in Turkey, leads to the development of medical problems that are mainly cardiovascular, gastrointestinal, systemic diseases, neurological and psychiatric or psychological, and coagulopathies.^10,12–15 Atherosclerosis is a chronic process involving both cellular and humoral responses. In atherogenesis, leucocytes are involved in the early phase of atherosclerosis and maintain their activity during plaque formation, during which time sICAM-1 and sVCAM-1 first co-ordinate leucocyte adhesion, then their transendothelial migration.¹ Both sICAM-1 and sVCAM-1 are transmembrane glycoproteins that bind to β-integrins found on the leucocyte surface. ICAM-1 is strongly upregulated by inflammatory cytokines in endothelial cells, fibroblasts, epithelial cells and multiple haemopoietic cells. Generally, in noninflammatory conditions, ICAM-1 is expressed on the surface of very few cells that might be important in the induction of this adhesion molecule. Its role is the regulation of various intercellular interactions that generate host immune responses. VCAM-1 is specific for mononuclear cells and functions as a ligand with an affinity for β 1 integrins, which are found in lymphocytes and monocytes. As is the case for ICAM-1, expression of VCAM-1 is modulated by many similar cytokines. However, distribution of VCAM-1 is contained in the activated endothelial cells in traumatized regions, and is more frequently observed in intimal layers of neovascular structures. Despite structural and functional similarities between ICAM-1 and VCAM-1, differences in their distribution pattern in tissues, their receptor specificities and their responses to haemodynamic forces are of critical importance in the pathogenesis of atherosclerosis.² A study demonstrated that increases in sICAM-1 levels might be predictive for myocardial infarction and stroke.¹⁶ However, the same evaluation is not valid for sVCAM-1.¹⁷ Investigators have reported that endothelial activation and inflammation are important precursors for the induction and progression of atherosclerosis, and have suggested that ICAM-1 and VCAM-1 may each play an independent role in the development of peripheral atherosclerosis.¹⁸

Adhesion process and transendothelial migration of leucocytes are mediated by cellular adhesion molecules (CAM). CAM are expressed on the surface of endothelial cells in response to various inflammatory cytokines, such as IL-1, TNF-α and IFN-γ. Intracellular CAM-1 and VCAM-1 are two prototype members of the immunoglobulin superfamily that have important roles in the accumulation of focal leucocytes in the subendothelial region.¹⁹ Increased plasma levels of ICAM-1 and VCAM-1 (and their soluble molecules) are indicators of inflammation, and also seem to be risk factors for further development of vascular occlusion in coronary artery disease.²⁰ E-selectin, which is another member of the adhesion molecule family expressed on the surface of endothelial cells, enables the involvement of leucocytes in inflammatory processes during an inflammatory response.²¹

Adhesion molecules play important roles in atherosclerosis and cancer. TNF-α is important in the onset of inflammation.²² Functions of the TNF-α signal pathway are mediated by nuclear factor-κB, which is also responsible for the endothelial expression of adhesion molecules such as ICAM-1 and VCAM-1.²¹ Increased expression of ICAM-1 may play an important role in the development of malignant tumours.^23–25 Although hypothyroidism has been reported to be responsible for an increased risk of atherosclerotic heart disease, outcomes of prospective studies are inconclusive.^26,27 One study revealed an association between SHO and atherosclerosis and myocardial infarction in older women,²⁶ and further studies have claimed that levothyroxine replacement therapy in those with manifest or SHO has improved atherosclerotic signs and symptoms.^21,28–30 In contrast, a 20-year follow-up study failed to find any correlation between TSH levels and ischaemic heart disease.³¹

Adhesion is important in the tumoural invasion of endothelial cells, and this process is mediated by ICAM-1 and E-selectin.^32,33 Generally, immune cells play a crucial role in the suppression of tumour metastases. ICAM-1 binds to lymphocytes to suppress immune cell functions, acting as an immunosuppressive substance. The correlation between ICAM-1 molecules and cancer cells, and the increase in ICAM-1 expression from cancer cells that is related to progression or metastases, have been used to support this view.³⁴ The correlation between soluble forms of adhesion molecules and tumour–node–metastasis staging, and also between development of metastasis in gastric, colorectal and breast cancers has also been demonstrated.^24,33,35

The aim of the present study was to determine the correlation between TSH levels and sICAM-1, sVCAM-1 and E-selectin values in patients with SHO. In patients with SHO, pretreatment sICAM-1 levels were found to be significantly higher than those found in healthy controls (P = 0.0001). Post-treatment sICAM-1 levels decreased significantly (P = 0.0001) after 3 months of levothyroxine therapy. In our study, the drop in sICAM-1 levels with levothyroxine reflects the favourable effects of treatment. The administration of levothyroxine therapy to those with SHO could prevent atherosclerotic processes and related cardiovascular diseases, and possibly prevent the future development of malignancy. s-ICAM is an indicator of the amount of inflammation in disease states; it is likely that levothyroxine use reduced the thyroid autoimmune process, as shown in our results through the post-treatment reduction in the sICAM-1 level.

Several potential limitations of our study should be addressed. First, the duration of our study was 3 months, which was very short. Second, the pre-and post-treatment antibody titres should have been defined in all patients. Another possible limitation is the fact that intima media thickness and high density lipoprotein/low density lipoprotein ratios were not defined, as these would provide further links to the role of adhesion molecules in the development of atherosclerosis and cancer. Future studies of longer duration, involving larger patient populations in which carotid intima thicknesses are assessed, are needed.

Footnotes

Declaration of conflicting of interest

The authors had no conflicts of interest to declare in relation to this article.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

References

Arem

Escalante

. Subclinical hypothyroidism: epidemiology, diagnosis and significance. Adv Intern Med 1996; 41: 213–250.

Ladenson

Singer

Ain

. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000; 160: 1573–1575.

Tunbridge

Evered

Hall

. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7: 481–493.

Pirich

Müllner

Sinzinger

. Prevalence and relevance of thyroid dysfunction in 1922 cholesterol screening participants. J Clin Epidemiol 2000; 53: 623–629.

Geul

van Sluisveld

Grobbee

. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf) 1993; 39: 275–280.

Chu

Crapo

. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab 2001; 86: 4591–4599.

Crockard

Boylan

. Corticosteroids effects on neutrophil adhesion molecules. Int J Clin Lab Res 1998; 28: 110–115.

Feldman

Intercelluler adhesion molecules. In: Roitt

Brastaff

Male

(eds). Immunology, Barcelona: Mosby, 1996, pp. 143–145.

Tanaka

Sakata

Morimoto

. Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules, ICAM-1 and VCAM-1. Planta Med 2001; 67: 108–113.

10.

Monzani

Caraccio

Del Guerra

. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy. Clin Endocrinol (Oxf) 1999; 51: 237–242.

11.

Klein

Chopra

. Alterations in tissue thyroxine-5'-monodeiodinating activity in perinatal period. Endocrinology 1978; 103: 235–239.

12.

Tappy

Randin

Skhwed

. Prevalance of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not with dementia. J Am Geriatr Soc 1987; 35: 526–531.

13.

Misiunas

Niepomniszcze

Ravera

. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995; 5: 283–286.

14.

Arem

Rokey

Kiefe

. Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: Effect of thyroid hormone therapy. Thyroid 1996; 6: 397–402.

15.

Foldes

Istvanfy

Halmagyi

. Hypothyroidism and the heart. Examination of left ventricular function in subclinical hypothyroidism. Acta Med Hung 1987; 44: 337–347.

16.

Pudil

Pidrman

Krejsek

. Cytokines and adhesion molecules in the course of acute myocardial infarction. Clin Chim Acta 1999; 280: 127–134.

17.

McDermott

Ridgway

. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001; 86: 4585–4590.

18.

vanBuul

van Rijssel

van Alphen

. Inside-out regulation of ICAM-1 dynamics in TNF-alpha-activated endothelium. PLoS One 2010; 5: e11336–e11336. . doi: 10.1371/journal.pone.0011336.

19.

Sheng

Wang

. Levels of soluble adhesion molecules in patients with various clinical presentations of coronary atherosclerosis. Chin Med J (Engl) 2010; 123: 3123–3126.

20.

Patel

Jindal

King

. The inflammatory response to double stranded DNA in endothelial cells is mediated by NFκB and TNFα. PLoS One 2011; 6: e19910–e19910. . doi: 10.1371/journal.pone.0019910.

21.

Monzani

Caraccio

Kozàkowà

. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2004; 89: 2099–2106.

22.

Mantur

Snarska

Koper

. Serum sICAM, sVCAM and sE-selectin levels in colorectal cancer patients. Folia HistochemCytobiol 2009; 47: 621–625.

23.

Bendas

Borsig

. Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012; 2012: 676731–676731. . doi: 10.1155/2012/676731.

24.

Jung

Jang

Kim

. Expression of intracellular adhesion molecule-1 and e-selectin in gastric cancer and their clinical significance. J Gastric Cancer 2012; 12: 140–148. doi: 10.5230/jgc.2012.12.3.140.

25.

Cappola

Ladenson

. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 2003; 88: 2438–2444.

26.

Hak

Pols

Visser

. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000; 132: 270–278.

27.

Kahaly

. Cardiovascular and atherogenic aspects of subclinical hypothroidism. Thyroid 2000; 10: 665–679.

28.

Ozcan

Cakir

Yaman

. The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism. Clin Endocrinol (Oxf) 2005; 63: 203–206.

29.

Gullu

Sav

Kamel

. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism. Eur J Endocrinol 2005; 152: 355–361.

30.

Akinci

Comlekci

Ali Ozcan

. Elevated thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels in overt and subclinical hypothyroid patients were reduced by levothyroxine replacement. Endocr J 2007; 54: 45–52.

31.

Vanderpump

Tunbridge

French

. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43: 55–68.

32.

Ferroni

Roselli

Spila

. Serum sE-selectin levels and carcinoembryonic antigen mRNA-expressing cells in peripheral blood as prognostic factors in colorectal cancer patients. Cancer 2010; 116: 2913–2921. doi: 10.1002/cncr.25094.

33.

Touvier

Fezeu

Ahluwalia

. Pre-diagnostic levels of adiponectin and soluble vascular cell adhesion molecule-1 are associated with colorectal cancer risk. World J Gastroenterol 2012; 18: 2805–2812. doi: 10.3748/wjg.v18.i22.2805.

34.

Frank

Lisanti

. ICAM-1: role in inflammation and in the regulation of vascular permeability. Am J Physiol Heart Circ Physiol 2008; 295: H926–H927. doi: 10.1152/ajpheart.00779.2008.

35.

Isoppo de Souza

Rosa

Ettrich

. Association of adipokines and adhesion molecules with indicators of obesity in women undergoing mammography screening. Nutr Metab (Lond) 2012; 9: 97–97. . doi: 10.1186/1743-7075-9-97.

Subclinical hypothyroidism: Comparison of adhesion molecule levels before and after levothyroxine therapy

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Patients and methods

Patients

Blood measurements

Treatment

Statistical analyses

Results

Discussion

Footnotes

Declaration of conflicting of interest

Funding

References