Markers of inflammation after zoledronic acid redosing.

The symptoms of acute phase response (APR) following the first infusion of zoledronic acid (ZA) are attenuated after re-administration. We investigated the reasons for this attenuation, focusing on the changes in several hormones, bone markers and markers of inflammation occurring after the second ZA injection in patients who had experienced a severe APR after their first ZA infusion. Twenty-two postmenopausal women with osteoporosis and severe symptoms of APR following the first ZA infusion were included in the study (group A1). A year later, the same women (possibly with a residual activity of ZA) were subjected to ZA re-administration (group A2). Urine NTx (uNTx), white blood cells, parathyroid hormone, serum calcium, phosphorus and several serum markers of inflammation were measured before (0) and at 1 and 2 days following the first as well as the second infusion. In group A1, the APR was associated with a significant increase in serum C-reactive protein (CRP), high-sensitive interleukin 6 (hsIL-6), high-sensitive tumor necrosis factor alpha (hsTNF-α) and cortisol within 24 h after the infusion. The majority of the patients in group A2 did not experience an APR and serum calcium, phosphorus, CRP, hsIL-6, hsTNF-α, and cortisol remained essentially unchanged throughout the study. In group A2, on day 0, the uNTx were significantly lower than in group A1. In group A1 the uNTx decreased by 69 and 78% from baseline on days 1 and 2, whereas in group A2, they decreased by 48 and 53% (p < 0.01), respectively. A positive correlation was found between the degree of uNTx decline from the baseline levels (Δ-uNTx) and hsTNF-α and between Δ-uNTx and CRP. The Δ-uNTx, reflecting the osteoclast-mediated bone resorption, may play some role in the APR appearance, although it must be excluded if the relationships of the changes between uNTx and hsTNF-α/CRP are coincidental effects and not causal.

Transient changes in thyroid functions tests after zoledronic acid infusion.

Zoledronic acid (ZA) induces an acute phase response in association with elevation of serum cytokines, which possibly alter the 3 types of iodothyronine deiodinase activity. We therefore studied the possible alteration in thyroid function tests by ZA. We investigated the acute changes in serum thyroid hormones, TSH, cortisol, white blood cells, CRP, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), before (0) and 1, 2 and 3 days after iv infusion of 5 mg ZA in 24 asymptomatic postmenopausal women with osteoporosis (ZA group) in comparison with a placebo group. In the majority of patients the ZA infusion was associated with acute phase response and fever within 24h after infusion which became attenuated on day three. Concurrently with increase in serum cortisol, CRP, IL-6 and TNF-α, on day 1 and 2, total serum T3 (TT3), free T3 (fT3), total T4 (TT4) and fT4 decreased with a nadir on day 2 in association with an increase in the fT4/fT3 ratio and reverse T3 (rT3) levels. All thyroid function changes returned to the baseline levels on day 3, with cytokines still at higher levels, although lower than those on day 2. Serum TSH remained essentially unchanged throughout the study. The changes in thyroid hormones were at least in part explained by the increased TNF-α, but not by IL-6. ZA induces short term changes in thyroid hormones, characteristic of nonthyroidal illness syndrome (NTIS), in association with an increase in TNF-α and IL-6.

Blood lymphocyte blastogenesis in patients with thyroid dysfunction: ex vivo response to mitogen activation and cyclosporin A.

OBJECTIVE: To evaluate lymphocyte activation following mitogen and cyclosporin A (CsA) administration in peripheral blood of hyperthyroxinaemic and hypothyroid patients. MATERIALS AND METHODS: Lymphocyte activation was evaluated by determining blastogenesis in 48 h cultured blood lymphocytes obtained from eight hyperthyroxinaemic and eight hypothyroid patients, following phytohaemagglutinin (PHA)-induced stimulation in the absence or presence of CsA. Twelve healthy volunteers served as controls. RESULTS AND CONCLUSIONS: Lymphocytes from hypothyroid patients exhibited reduced response to PHA and lower sensitivity to CsA compared with control, which could be attributed to their reduced activation capability coexisting with hypothyroidism. In hyperthyroxinaemic samples, the actions of high CsA concentrations were mostly targeted toward activated lymphoblasts. Considering the cellular targets that thyroid hormones and CsA may share, the therapeutic implications of their cross-talk need careful consideration.

Changes in risk factors and Tumor Node Metastasis stage of sporadic medullary thyroid carcinoma over 41 years, before and after the routine measurements of serum calcitonin.

The measurement of serum calcitonin (CT) in all thyroid nodules for the detection of medullary thyroid carcinoma (MTC) is controversial. We compare several prognostic factors, Tumor Node Metastasis (TNM) stage, and survival in sporadic MTC patients operated on before and after the use of routine measurements of serum CT in combination with thyroid ultrasonography (US). Thirty-seven patients had been operated on between 1969 and 1989 (group I), before the use of routine measurements of serum CT and the routine use of thyroid US, and 39 (group II) had been operated on between 1990 and 2009, after the introduction of routine use of serum CT and thyroid US. There were no between-group differences concerning age and sex. Group I had larger tumors at the time of operation (P < .001) and higher postoperative serum CT levels (P < .001). Cervical lymph node and distant metastases were found more frequently in group I in comparison with group II. The cases with TNM stage I were significantly higher in group II than in group I, in contrast with the cases with TNM stage IV that were significantly higher in group I. Univariate analysis revealed a significantly higher 15-year survival rate in group II than in group I (P = .002). The postoperative CT levels were positively correlated with tumor size (P < .001). During the last 2 decades, the diagnosis of sporadic MTC at an earlier stage has been made possible by the routine use of serum CT in combination with thyroid US. The significant increase of the 15-year survival rate shows better outcome in these patients.

The effects of recombinant human TSH on bone turnover in patients after thyroidectomy.

Thyrotropin receptors are expressed in several extrathyroidal tissues including bone. We investigated whether the increase of thyroid-stimulating hormone (TSH) levels, under stable thyroid hormone levels, affects the bone markers. Thirty-two postmenopausal women, with papillary thyroid carcinoma, previously treated with near-total thyroidectomy and I131 remnant ablation underwent routine evaluation for residual disease by using injections of recombinant human TSH (rhTSH) without withdrawal from thyroxine therapy. Changes in TSH levels and various serum and urine markers of bone metabolism were followed before and 1, 2, 5, and 7 days after the rhTSH injections. A transient, significant decrease in serum calcium and urinary excretion of C- and N-terminal telopeptides of type I collagen was observed after the injections of rhTSH. Serum parathyroid hormone (PTH) started to rise along with TSH, but a significant increase of PTH was only reached on Day 5 when the TSH concentration had fallen more than 80% of the peak value. Bone alkaline phosphatase and osteocalcin did not show any significant change over time. There was no significant correlation between TSH concentration and the various parameters we measured. The study provides evidence that rhTSH produces a transient inhibition of bone resorption, as well as an attenuation of osteoblast response in spite of the PTH activation. Additional studies are needed to resolve the mechanisms by which TSH alters the response of the bone cells.

Helicobacter pylori infection and endocrine disorders: is there a link?

Helicobacter pylori (H pylori) infection is a leading world-wide infectious disease as it affects more than half of the world population and causes chronic gastritis, peptic ulcer disease and gastric malignancies. The infection elicits a chronic cellular inflammatory response in the gastric mucosa. However, the effects of this local inflammation may not be confined solely to the digestive tract but may spread to involve extra-intestinal tissues and/or organs. Indeed, H pylori infection has been epidemiologically linked to extra-digestive conditions and diseases. In this context, it has been speculated that H pylori infection may be responsible for various endocrine disorders, such as autoimmune thyroid diseases, diabetes mellitus, dyslipidemia, obesity, osteoporosis and primary hyperparathyroidism. This is a review of the relationship between H pylori infection and these endocrine disorders.

L-thyroxine therapy attenuates the decline in serum triiodothyronine in nonthyroidal illness induced by hysterectomy.

It is controversial whether the administration of thyroid hormone to patients with nonthyroidal illness has any beneficial effect. Two groups of patients undergoing abdominal hysterectomy under the same general anesthesia were studied. Group A consisted of 15 women taking chronically l-thyroxine therapy (1.8 mug/kg daily), and group B (control) consisted of 16 apparently healthy euthyroid women taking placebo. Thyroid hormones, cortisol, and interleukin (IL)-6 were measured 1 day before and 1, 2, 3, and 6 days after surgery. Total triiodothyronine (TT(3)) decreased to a significantly greater degree (P <.05) and for a longer period of time in group B than in group A. The significant increase of reverse T(3) (rT(3)) noted early in group B failed to reach the baseline levels until the end of the study, whereas in group A, rT(3) returned to the preoperative values by day 2. Both groups had similar free thyroxine (FT(4)) at baseline. FT(4) increased significantly at day 1 and remained significantly elevated throughout the postoperative period in group B only. Serum TT(4), thyroid-stimulating hormone (TSH), and cortisol did not change significantly in either group. In all patients, IL-6 increased significantly to a peak value at day 1, showing a slow decrease thereafter. A stronger negative correlation was found between T(3) and IL-6 in group B than in group A (r = -.66, P <.0001 v r = -.38, P <.001, respectively) and a strong positive correlation was observed between rT(3) and IL-6 in group B only (r =.57, P <.001). The long-term treatment with T(4) seems to attenuate the decrease of serum T(3), which occurs during the development of nonthyroidal illness postoperatively. The elevation of IL-6 accounted for a greater proportion of the variations of the T(3) and rT(3) in the control group B than in the T(4)-treated group A.