| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Technical Briefs |
1 Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital of Zurich, CH-8091 Zurich, Switzerland
aauthor for correspondence: fax 41-1-255-4447, e-mail peter.wiesli{at}dim.usz.ch
Hypothyroidism is associated with endothelial dysfunction, arterial hypertension, and impaired kidney function (1)(2)(3). An increased serum creatinine and decreased glomerular filtration rate and renal blood flow have been described (2)(4)(5). These deleterious consequences may result from several mechanisms, including direct and indirect effects of thyroid hormones on blood vessels. Insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF), growth factors with both local and systemic effects, may be involved as potential mediators. Hypothyroidism causes low concentrations of IGF-1, which can be normalized by thyroxine replacement therapy (6). IGF-1 is known to increase forearm blood flow and creatinine clearance in humans (7)(8)(9). VEGF increases endothelial nitric oxide synthase activity, contributing to the relaxing capacity of the renal vasculature (10)(11)(12)(13). Thus, both IGF-1 and VEGF may improve endothelial function and renal blood flow.
The purpose of this study was to test the effect of thyroxine therapy on serum creatinine, IGF-1, and VEGF in hypothyroid patients. Patients with newly diagnosed primary hypothyroidism who had been referred to the Division of Endocrinology and Diabetes at the University Hospital in Zurich between February 1998 and July 2002 were included in this prospective case series. Oral informed consent was obtained from all patients. Patients with neoplastic disease, secondary hypothyroidism, and thyroid cancer were excluded from the study because VEGF is often increased in patients with tumors, including tumors of the pituitary gland and the thyroid (14)(15).
All laboratory values were measured in the hypothyroid and the euthyroid state. Thyrotropin (TSH), free thyroxine (fT4), creatine kinase, and creatinine were measured at the Central Laboratory of the University Hospital of Zurich with standard methods. For IGF-1 measurements, carrier proteins were removed by Sep-Pak® chromatography according to the instructions of the supplier (Waters Associates), and IGF-1 was measured by RIA (16) with a reference interval of 100–300 µg/L in adults. Acid-labile subunit (ALS) was measured by an active total ALS ELISA, an enzymatically amplified "two-step" sandwich-type immunoassay (Diagnostic Systems Laboratories) with a reference interval of 12–35 µg/L for individuals 16–60 years of age. Serum VEGF concentrations were measured with a commercially available ELISA (R&D Systems). The reference interval provided by the manufacturer was 62–707 ng/L, determined in serum samples of 37 healthy individuals. We measured VEGF in serum samples from 21 healthy individuals, and the values were between 42 and 1158 ng/L. Statistical analyses were performed using SAS, Ver. 8.2 (SAS Institute Inc.). Data are presented as means (SD). Differences between values before and after thyroxine replacement therapy were analyzed with the two-sided paired t-test except when the variables were not normally distributed, in which case the Wilcoxon signed-rank test was used. A P value <0.05 was considered statistically significant.
Fourteen patients (7 males and 7 females) with primary hypothyroidism were included. Mean (SD) age at diagnosis was 41 (16) years. Three patients were on antihypertension drugs; the treatment remained unchanged during the study period. At first presentation, all patients were symptomatic with low fT4 and high TSH. Mean (SD) fT4 was 3.8 (2.6) pmol/L (reference interval, 12–22 pmol/L), and TSH was 312 (277) mIU/L (reference interval, 0.27–4.2 mIU/L). All patients were treated with thyroxine and were, on average, euthyroid within 34 (20) weeks of replacement therapy. Mean fT4 in the euthyroid state was 18.9 (4) pmol/L, and TSH was 2.7 (1.9) mIU/L. Creatine kinase concentrations, which were increased in 11 patients at baseline, returned to values within the reference interval. Mean blood pressure was 124/82 mmHg in the hypothyroid and 121/75 mmHg in the euthyroid state (P = 0.01 for diastolic blood pressure). Mean heart rate was 64 (10) beats/min at diagnosis of hypothyroidism and increased to 71 (10) beats/min after thyroxine treatment (P = 0.02).
The changes in serum creatinine, VEGF, IGF-1, and ALS after thyroxine replacement therapy are shown in Fig. 1
. Serum creatinine was above the reference interval at diagnosis of hypothyroidism in 9 of the 14 patients and decreased from 116 (27) to 93 (17) µmol/L (reference interval, 60–105 µmol/L) after thyroxine replacement (P = 0.001). Serum creatinine decreased in all 14 patients but remained slightly above the reference interval in 3 patients.
|
IGF-1 was below the reference interval in eight patients at diagnosis of hypothyroidism and increased from 108 (62) to 159 (59) µg/L (P = 0.01). ALS was below the age-adjusted reference interval in five patients and increased from 14.2 (4.3) to 17.3 (4.3) mg/L (P = 0.008). IGF-1 increased in 12 and ALS in 13 patients. In the same period, VEGF increased from 326 (215) to 508 (456) ng/L (P = 0.005); these values were (at baseline) and remained (with treatment) within the reference interval of healthy individuals. VEGF increased in 13 of 14 patients.
IGF-1 concentrations are decreased in hypothyroidism and can be normalized by thyroxine replacement (17)(18)(19)(20). We have now extended the findings to the ALS of the 150-kDa IGF carrier complex. On average, ALS concentrations increased significantly after thyroxine replacement therapy. To our knowledge, this is the first description of the influence of thyroxine replacement on ALS. In the setting of primary hypothyroidism, the data do not allow differentiation between an effect of thyroid hormones on the pituitary (on growth hormone secretion) or the liver, but it appears to be a coordinated up-regulation of IGF-1 and ALS. IGF-1 has effects in addition to growth, including effects on endothelial function and renal blood flow. NO mediates some of the effects of IGF-1 on glomerular hemodynamics. IGF-1 induces NO synthesis and release by cultured vascular endothelial cells (21). Coadministration of the NO synthase inhibitor NG-nitro-L-arginine methyl ester blocked the IGF-1-induced increase in renal blood flow (22). A decrease in peripheral vascular resistance and in diastolic blood pressure may also be related to enhanced NO production and has been found in hypothyroid patients treated with thyroxine (23)(24)(25).
To the best of our knowledge, the increase in VEGF (within the reference interval) in response to thyroxine replacement had not been described before. A limitation of the present study is that VEGF was determined in serum and not in plasma. However, this limitation was true for all individuals investigated. Serum VEGF concentrations have been found to be much higher than those in plasma because of the release of platelet- and leukocyte-derived VEGF during blood clotting (26). Therefore, possible explanations for the increase in serum VEGF after thyroxine treatment include effects of thyroid hormones on the amount of VEGF transported and/or released from blood cells, e.g., by affecting thrombopoiesis or platelet aggregation (27)(28).
VEGF receptors are expressed on quiescent endothelia of glomerular capillaries in the kidney and therefore might have functions other than mediating endothelial growth (29). Our data demonstrate that IGF-1 and VEGF increase in response to thyroxine replacement in patients with primary hypothyroidism. IGF-1 and VEGF increased consistently in almost every individual treated, whereas serum creatinine concentrations decreased within the same period. In our data, we found a significant relationship between creatinine and VEGF after adjusting for IGF-1, age, and sex. In vivo and in vitro studies have shown that IGF-1 and VEGF may improve endothelial function and renal blood flow, whereas other studies have shown that endothelial function and renal blood flow are impaired in thyroid hormone deficiency (1)(10)(30). The increases in IGF-1 and VEGF in response to thyroxine may improve endothelial function and renal blood flow, thereby contributing to the observed reduction in diastolic blood pressure and decrease in serum creatinine in hypothyroid patients treated with thyroxine.
Acknowledgments
This work was supported by the Swiss National Science Foundation (Grant 32-46808.96).
References
The following articles in journals at HighWire Press have cited this article:
|
|
 |
|
  Y. Debaveye, B. Ellger, L. Mebis, E. Van Herck, W. Coopmans, V. Darras, and G. Van den Berghe Tissue Deiodinase Activity during Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone-Releasing Peptide-2 Endocrinology, December 1, 2005; 146(12): 5604 - 5611. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
