Andre J. Van Herle

The Thyroid Nodule

Abstract The various techniques for evaluating a thyroid nodule are described and their relative values analyzed. Fine-needle aspiration is the most sensitive and specific test among the leading te...

The comparative value of serum thyroglobulin measurements and iodine 131 total body scans in the follow-up study of patients with treated differentiated thyroid cancer

This study is an attempt to unify the evaluation of patients with well-differentiated thyroid cancer after ablative therapy. As such serum thyroglobulin determinations on and off thyroid hormone (T4) therapy and iodine 131 total body scans were examined in 53 patient studies. No metastases were found in patients whose thyroglobulin value was undetectable (less than 1 ng/ml). Values during T4 therapy that were detectable, even as low as 4.2 ng/ml, were occasionally associated with metastases. After T4 withdrawal, thyroglobulin value and scan were obtained. Neither metastasis nor clinically detectable cancer was found in patients whose thyroglobulin value was less than 10 ng/ml while off T4. Conversely, a value greater than 10 ng/ml was often associated with documented metastases even when the scan was negative. In summary, a thyroglobulin value less than 1 ng/ml during T4 therapy or less than 10 ng/ml off T4 therapy suggests successful therapy and a routine scan could be avoided unless clinically indicated. However, a value greater than 10 ng/ml suggests the presence of metastasis despite a negative scan. Thyroglobulin determination substantially improves the management of these patients.

Serum prolactin levels in untreated primary hypothyroldism

Abstract The serum prolactin level was found to be elevated (>14.0 ng/ml) in 39 per cent of patients with untreated primary hypothyroidism, none of whom were receiving drugs known to affect serum prolactin levels. The mean serum thyroid-stimulating hormone (TSH) (± SEM), thyroxine (T 4 ) and triiodothyronine (T 3 ) levels prior to therapy were, respectively, 106.0 μU/ml ± 19.3, 0.9 μg/dl ± 0.2, 50.6 ng/dl ± 5.8. The mean serum prolactin level in the hypothyroid group (14.3 ng/ml ± 1.1; range: 4.7 to 42.0 ng/ml; 49 subjects) was significantly higher (P

Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages.

Nearly one‐half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25‐dihydroxyvitamin D (1,25(OH)2D3). However, the cellular source of the vitamin D hormone in lymphomas remains unclear. To address this, we report the case of a 75‐year‐old man with hypercalcemia associated with raised circulating concentrations of 1,25(OH)2D3 and suppressed parathyroid hormone (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT) imaging revealed the presence of a large lymphoma that was confined to the spleen; subsequent pathological analysis showed that this was an intermediate grade B‐cell lymphoma. After surgical removal of the spleen, serum calcium and 1,25(OH)2D3 levels became normalized within 24 h. Immunolocalization of the vitamin D‐activating enzyme 25‐hydroxyvitamin D3‐1α‐hydroxylase (1α‐hydroxylase) in sections of resected spleen showed that staining was negative in the lymphoma cells but positive in neighboring macrophages. This case study indicates that the hypercalcemia associated with lymphomas may be due, in some instances, to excessive extrarenal production of 1,25(OH)2D3. Furthermore, by using immunohistochemistry to assess the distribution of 1α‐hydroxylase, we have been able to show for the first time that tissue macrophages, rather than actual tumor cells, are the most likely ectopic source of this enzyme. Based on this case study, we propose that the abnormal synthesis of 1,25(OH)2D3 associated with some lymphomas is because of paracrine regulation of tumor‐associated macrophages.

Regulation of the Growth Arrest and DNA Damage-Inducible Gene 45 (GADD45) by Peroxisome Proliferator-Activated Receptor γ in Vascular Smooth Muscle Cells

Abstract— Peroxisome proliferator-activated receptor (PPAR) &ggr; is activated by thiazolidinediones (TZDs), widely used as insulin-sensitizing agents for the treatment of type 2 diabetes. TZDs have been shown to induce apoptosis in a variety of mammalian cells. In vascular smooth muscle cells (VSMCs), proliferation and apoptosis may be competing processes during the formation of restenotic and atherosclerotic lesions. The precise molecular mechanisms by which TZDs induce apoptosis in VSMCs, however, remain unclear. In the present study, we demonstrate that the TZDs rosiglitazone (RSG), troglitazone (TRO), and a novel non-TZD partial PPAR&ggr; agonist (nTZDpa) induce caspase-mediated apoptosis of human coronary VSMCs. Induction of VSMC apoptosis correlated closely with an upregulation of growth arrest and DNA damage-inducible gene 45 (GADD45) mRNA expression and transcription, a well-recognized modulator of cell cycle arrest and apoptosis. Using adenoviral-mediated overexpression of a constitutively active PPAR&ggr; mutant and the irreversible PPAR&ggr; antagonist GW9662, we provide evidence that PPAR&ggr; ligands induce caspase-mediated apoptosis and GADD45 expression through a receptor-dependent pathway. Deletion analysis of the GADD45 promoter revealed that a 153-bp region between −234 and −81 bp proximal to the transcription start site, containing an Oct-1 element, was crucial for the PPAR&ggr; ligand–mediated induction of the GADD45 promoter. PPAR&ggr; activation induced Oct-1 protein expression and DNA binding and stimulated activity of a reporter plasmid driven by multiple Oct-1 elements. These findings suggest that activation of PPAR&ggr; can lead to apoptosis and growth arrest in VSMCs, at least in part, by inducing Oct-1–mediated transcription of GADD45. The full text of this article is available online at http://www.circresaha.org.

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

We previously reported that the PPARγ agonist troglitazone (TRO) inhibits proliferation and induces apoptosis in human MCF-7 breast carcinoma cells. To understand the mechanisms of antiproliferative and pro-apoptotic effects of TRO, we screened a limited DNA array containing 23 genes involved in regulating either the cell cycle and/or apoptosis. Four of the 23 genes screened exhibited regulation by TRO, with growth arrest and DNA damage-inducible gene 45 (GADD45) being the most strongly upregulated. TRO induced GADD45 mRNA expression in a time- and dose-dependent manner. Depletion of GADD45 by siRNA abrogated TRO-induced apoptosis in MCF-7 cells demonstrating the physiological relevance of GADD45 upregulation. Signaling pathways mediating TRO-induced GADD45 were also investigated. Several mitogen-activated protein kinase (MAPK) pathways were involved in the induction of GADD45 by TRO. Inhibition of the c-jun N-terminal kinase MAPK pathway by SP600125 partially abolished TRO-induced GADD45 mRNA, and protein expression and apoptosis. In contrast, inhibition of the p38 MAPK pathway by SB203580, or through overexpression of a dominant-negative mutant of p38 MAPK, augmented GADD45 mRNA induction and GADD45 promoter activation as well as cell apoptosis by TRO. Blockade of the extracellular signal-regulated kinase MAPK pathway by PD98059 also enhanced TROs effects on GADD45 and apoptosis. Two other PPARγ agonists pioglitazone and rosiglitazone did not induce GADD45 expression. Our finding of GADD45 induction by TRO may provide a new insight concerning the mechanisms for TROs antiproliferative and pro-apoptotic effects in breast cancer cells.

MEMORY IMPROVEMENT WITH TREATMENT OF HYPOTHYROIDISM

The consequences of inadequate thyroid hormone availability to the brain and treatment effects of levothyroxine on cognitive function are still poorly understood. This study prospectively assessed the effects of thyroid replacement therapy on cognitive function in patients suffering from biochemical evidenced, untreated hypothyroidism. Significant effects between the untreated hypothyroid group and control group were limited to verbal memory retrieval. When assessing the effects of 3-month treatment, results revealed that the treated hypothyroid group had significant increased verbal memory retrieval. Results suggest that specific memory retrieval deficits associated with hypothyroidism can resolve after replacement therapy with levothyroxine.

Serum Cortisol Levels in Cushing's Syndrome After Low- and High-Dose Dexamethasone Suppression

To standardize the cutoff points of serum cortisol values in the evaluation of Cushings syndrome during a low- and high-dose dexamethasone suppression test, daily serum cortisol measurements (0800 hours and 1600 hours) and urinary 17-hydroxycorticosteroids were compared (Study A). Forty-seven subjects were studied (11 normal subjects, 15 patients with Cushings disease, five patients with adrenal adenoma, and 16 subjects with suspected Cushings syndrome). A serum cortisol measurement at 1600 hours of more than 5 micrograms/dL on low-dose dexamethasone suppression and more than 10 micrograms/dL on high-dose dexamethasone were ascertained to be nonsuppressed values. A baseline dehydroepiandrosterone-sulfate value less than 0.4 microgram/mL indicated patients with an adrenocorticol adenoma. Study B was a prospective study of 17 patients in which no urine samples were collected. Serum cortisol levels, obtained in 1600 hours on the second day of low- and high-dose dexamethasone, accurately allowed a differential diagnosis of suspected Cushings syndrome. Serum cortisol measurements can replace the urinary 17-hydroxycorticoid measurements in a cost-effective manner without a decrease in the degree of accuracy.

Thyroid Physiology in Health and Disease

Abstract The pituitary thyrotrophin reserve in 55 patients was tested with thyrotrophin-releasing hormone, and only 28% with deficient responses were hypothyroid; in three patients with hypothalami...

Cyclic cushing's syndrome

Cyclic Cushings syndrome is a rare but increasingly recognized disorder of periodic fluctuations of adrenal steroid production. A case of cyclic Cushings syndrome due to a pituitary adenoma is described. The patient demonstrated a prolonged cycle length of approximately six months, during which a spontaneous remission occurred both clinically and biochemically. Previously documented cases of cyclic Cushings syndrome are reviewed, and the pitfalls in interpretation of results of dexamethasone suppression testing in the presence of spontaneous fluctuations in cortisol production are discussed.