Thyroid nodules are common and occur in up to 50% of the adult population; however, less than 7% of thyroid nodules are malignant. High-resolution ultrasonography (US) is commonly used to evaluate the thyroid gland, but US is frequently misperceived as unhelpful for identifying features that distinguish benign from malignant nodules. Microcalcifications are one of the most specific US findings of a thyroid malignancy. Other useful US features include a marked hypoechogenicity, irregular margins, and the absence of a hypoechoic halo around the nodule. Lymphadenopathy and local invasion of adjacent structures are highly specific features of thyroid malignancy but are less commonly seen. The number, size, and interval growth of nodules are nonspecific characteristics. Suspicious US features may be useful for selecting patients for fine-needle aspiration biopsy when incidental nodules are discovered and when multiple nodules are present. Common interpretative pitfalls that may lead to failure to recognize a malignancy include mistaking cystic or calcified nodal metastases for nodules in a multinodular thyroid, mistaking diffusely infiltrative thyroid carcinomas and multifocal carcinomas for benign disease, and failing to recognize microcalcifications in papillary thyroid cancer.

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US Features of Thyroid Malignancy: Pearls and Pitfalls

Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARγ, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body-weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARγ-modulating drugs.

Thiazolidinediones and PPARγ agonists: time for a reassessment

Diabet. Med. 27, 309–317 (2010)



Abstract

Aims  Baseline glycated haemoglobin (HbA1c) concentrations vary between clinical trials of glucose-lowering agents and this may affect interpretation of clinical efficacy. The objective of this study is to quantify the relationship between baseline HbA1c and reduction of HbA1c in clinical trials.



Methods  PubMed literature searches from 1991 to 2007. Randomized controlled studies with placebo-controlled or comparator arms [≥ 9 patients in the intent-to-treat (ITT) population] ranging in duration from 23 to 52 weeks, in which baseline and change in glycated haemoglobin (HbA1c) were reported. The relationship between baseline HbA1c and change in HbA1c was analysed by a weighted least-squared regression model accounting for ITT population and variance of HbA1c change. Fourteen per cent of independently abstracted studies met the selection criteria.



Results  Meta-analysis from 59 clinical trials (8479 patients) produced weighted R2 of 0.35 (P < 0.0001) for the association of baseline HbA1c and absolute change in HbA1c. Subanalysis of eight metformin clinical trials demonstrated a stronger association [weighted R2 of 0.67 (P = 0.0130)]. Exclusion of metformin clinical trials from the overall meta-analysis (n = 51) yielded a weighted R2 of 0.31 (P < 0.0001). Subanalyses of clinical trials of glucose-lowering therapies predominantly targeting fasting (n = 37) or postprandial (n = 22) blood glucose produced weighted R2 values of 0.27 (P < 0.001) and 0.42 (P < 0.005), respectively.



Conclusions  These data demonstrate a positive relationship between baseline HbA1c and the magnitude of HbA1c change across 10 categories of glucose-lowering therapies, irrespective of class or mode of action. These observations should be considered when assessing clinical efficacy of diabetes therapies derived from clinical trials.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1464-5491.2009.02941.x

Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials.

Importance of the field: Thiazolidinediones (TZDs) are useful glucose-lowering agents for patients with Type 2 diabetes. Through PPAR-γ-mediated effects, these drugs not only improve insulin sensitivity and glycemia, they also have beneficial effects on lipid metabolism and the vascular endothelium, with potential to improve cardiovascular risk. However, this promise has not been entirely fulfilled. The first TZD, troglitazone, was withdrawn after reports of severe liver damage. The second TZD, rosiglitazone, has been reported in meta-analyses to be associated with possible increased risk of cardiovascular disease (CVD) events. The third TZD approved for clinical use in the US, pioglitazone, appears to be associated with decreased CVD events in most studies/meta-analyses.Areas covered in this review: We undertook a literature search in Pubmed from the year 2000 onwards to review the side effect/safety profile of pioglitazone.What the reader will gain: A comprehensive summary of the currently available dat...

Pioglitazone: side effect and safety profile

Thyroid cancer can be associated with thyrotoxicosis caused by Graves’ disease, toxic multinodular goiter, or autonomously functioning thyroid adenoma. The objective of this study was to summarize current evidence regarding the association of thyroid cancer and hyperthyroidism, particularly with respect to the type of hyperthyroidism found in some patients, and whether this affects the outcome of the patient. A PubMed search was performed up to August 2011. Articles were identified using combinations of the following keywords/phrases: thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, hyperthyroidism, Graves’ disease, auto­nomous adenoma, toxic thyroid nodule, and toxic multinodular goiter. Original research papers, case reports, and review articles were included. We concluded that the incidence, as well as the prognosis of thyroid cancer associated with hyperthyroidism is a matter of debate. It seems that Graves’ disease is associated with larger, multifocal, and potentially more aggressive thyroid cancer than single hot nodules or multinodular toxic goiter. Patients with Graves’ and thyroid nodules are at higher risk to develop thyroid cancer compared to patients with diffuse goiter. Every suspicious nodule associated with hyperthyroidism should be evaluated carefully.

/pdf/thyroid-cancer-in-patients-with-hyperthyroidism-5451rt25y3.pdf

Thyroid cancer in patients with hyperthyroidism.

It is well known that pioglitazone, a potent thiazolidinedione, improves metabolic control. However, weight gain or peripheral edema may be of major clinical concern when using this agent. The purpose of our study was to prospectively evaluate the effects of low-dose pioglitazone (7.5 mg/day) on metabolic control, weight gain and the incidence of edema compared with a standard dose of pioglitazone (15.0 mg/day) in patients with type 2 diabetes mellitus (T2DM). Ninety-five Japanese female patients (mean age 58.4 +/- 10.4 years) with newly diagnosed T2DM were selected for this study. They were randomly divided into the following 2 groups according to therapy regimens, and examined every month for 6 months after diagnosis. Group A consisted of 54 patients treated with low-dose pioglitazone orally; Group B, the control-group, consisted of 41 patients treated with standard-dose pioglitazone orally. The incidence of peripheral edema was significantly much lower in group A (2/54) than in group B (11/41) (p = 0.0014). In addition, % change of body weight during the 6-month treatment in group A was significantly less than that in group B (p < 0.0001). On the other hand, the % change of biochemical parameters including HbA1c did not differ significantly between group A and group B, although glucose and lipid control significantly improved from baseline in both groups. Our results demonstrate the safety and efficacy of low-dose pioglitazone, suggesting that it could be another good choice of treatment for Japanese women with T2DM.

Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/day) in japanese women with type 2 diabetes mellitus

A 59-year-old woman with papillary thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this report. The patient was referred to our clinic because of rapid weight loss and swelling on the left side of the neck. Ultrasonography of the thyroid demonstrated a nonhomogeneous nodule in the lower part of an enlarged left lobe. Both 99mTc and 123I thyroid scintigraphic imaging showed a hot area corresponding to the nodule with lower uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed papillary adenocarcinoma, and the immunohistochemistry proved weak but positive staining for triiodothyronine and thyroxine. Based on these findings, the nodule was diagnosed as a functioning papillary adenocarcinoma. Although thyroid carcinoma manifesting as a hot nodule on the radionuclide isotope scan is an extremely rare occurrence, the current case is clinically important because it suggests that the diagnosis of a hot nodule cannot always rule out thyroid carcinoma in the nodule, and that even a hot nodule requires careful management so that the malignancy is not overlooked.

Papillary thyroid carcinoma without metastases manifesting as an autonomously functioning thyroid nodule

It has been well established that hyperthyroidism leads to diminished bone mineral density (BMD), and that a previous history of hyperthyroidism remains a risk factor for fractures. However, little is known about how to manage the reduction in BMD caused by hyperthyroidism. The purpose of this study was to evaluate the efficacy of risedronate for the treatment of osteoporosis/osteopenia in patients with Graves' disease (GD). Of 34 Japanese male patients with newly diagnosed GD, 27 with osteoporosis/osteopenia were included in this study. They were randomly divided into two groups by therapeutic regimen. Group A consisted of 14 patients treated with an antithyroid drug and risedronate. Group B consisted of 13 patients treated with the same antithyroid drug only. We used dual-energy X-ray absorptiometry to measure BMD at the lumber spine, femoral neck, and distal radius at baseline, and at 6 and 12 months after the trial. Bone-specific alkaline phosphatase and urinary N-terminal telopeptide of type I collagen normalized by creatinine were significantly more reduced in group A than in group B after both 6 and 12 months. The percentage increases in BMD at the lumbar spine and distal radius were significantly greater in group A than in group B. These beneficial effects of risedronate for patients with osteoporosis/osteopenia caused by GD may lead to a reduced risk of future fractures. We thus conclude that risedronate should be considered for the treatment of decreased bone mass associated with GD.

Clinical significance of risedronate for osteoporosis in the initial treatment of male patients with Graves' disease.

Although it has been established that hyperthyroidism leads to reduced bone mineral density (BMD), with accelerated bone turnover promoting bone resorption in female patients, there is a dearth of data for male patients with hyperthyroidism. This study evaluated BMD and bone metabolism in male patients with Graves’ disease. The study included 56 Japanese male patients with newly diagnosed Graves’ disease and 34 normal Japanese male control subjects of similar age and body mass index. We used dual energy x-ray absorptiometry to measure BMD at sites with different cortical/cancellous bone ratios (lumbar spine, femoral neck, and distal radius). At the lumbar spine and the distal radius, BMD and T-scores were significantly lower for patients than for controls. At the femoral neck, on the other hand, the same values were relatively, but not significantly, lower in patients than in controls. However, Z-scores at all three sites were significantly lower for patients than for controls. The Z -score at the distal radius of patients was significantly lower than that at their lumbar spine and femoral neck. In addition, Z-score at the distal radius correlated negatively with age, free thyroxine, thyroid stimulating hormone receptor antibodies, thyroid stimulating antibody, and urinary N-terminal telopeptide of type I collagen normalized by creatinine. These results indicate a high prevalence of cortical bone loss in male patients with Graves’ disease, especially elderly patients. We conclude that BMD measurement is crucial in all Graves’ disease patients regardless of their gender and that the radial BMD as well as BMD at the lumbar spine and femoral neck should be monitored to effectively prevent bone loss and subsequent fracture.

Jerry Corners

Papers

Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/day) in japanese women with type 2 diabetes mellitus

Papillary thyroid carcinoma without metastases manifesting as an autonomously functioning thyroid nodule

Clinical significance of risedronate for osteoporosis in the initial treatment of male patients with Graves' disease.

Negative correlation between bone mineral density and TSH receptor antibodies in male patients with untreated Graves' disease.