Review of oral cholecystographic agents for the management of hyperthyroidism.

OBJECTIVE: Although the use of oral cholecystographic agents (OCAs) had declined due to limited availability, there is literature to suggest it is an effective medication for thyrotoxicosis in appropriate clinical situations. METHODS: The authors performed a PubMed search and systematically reviewed all the English written case reports, original studies and reviews from 1953 to 2012. Additional information was supplemented from available online pharmacologic databases. RESULTS: The off-label use of OCAs was reviewed for the management of neonatal and adult Graves' disease, subacute thyroiditis, amiodarone-induced thyroiditis (AIT), exogenous hyperthyroidism, toxic multinodular goiter (TMNG), thyrotropinoma, thyrotoxicosis during pregnancy, rapid pre-operative control of hyperthyroidism, and thyroid storm. Adverse effects were also reviewed. CONCLUSION: OCAs generally are effective agents in treating thyrotoxicosis in the etiologies reviewed. OCAs are clinically relevant in patients who require rapid control, such as in the pre-operative state or patient who cannot tolerate a thyrotoxicosis state. OCA may also be beneficial in situations where other anti-thyroidal medication would be hazardous or ineffective, such as thionamide allergy or exogenous thyrotoxicosis. Given concern for long-term relapse, OCAs should be considered a short-term bridge to definitive therapy. OCAs are limited in TMNG and should be second line after glucocorticoids in AIT II. OCAs do not preclude the use of radioactive iodine, which can be performed one week after OCA therapy.

Physiological roles of parathyroid hormone-related protein.

BACKGROUND: Parathyroid hormone related peptide (PTHrP) is widely expressed in a variety of normal fetal and adult tissues. AIM OF WORK: Review of these normal physiologic functions of PTHrP in each of these tissues. METHOD: Performed literature search on pubmed on articles related to PTHrP and physiologic roles. RESULTS: PTHrP is expressed in wide range of sites in the body with roles including relaxation of vessels and smooth muscle cells, and regulation of development. PTHrP also mediates humoral hypercalcemia of malignancy. PTHrP can be falsely elevated in benign conditions. Lastly, PTHrP has a pharmacological role in osteoporosis treatment. CONCLUSIONS: PTHrP has many various physiological roles besides mediating humoral hypercalcemia of malignancy. (www.actabiomedica.it).

Combined Pharmacologic Therapy in Postmenopausal Osteoporosis.

Antiresorptive agents for treating postmenopausal osteoporosis include selective estrogen receptor modulator (SERM), bisphosphonates and denoumab. Teriparatide is the only Food and Drug Administration-approved anabolic agent. Synergistic effects of combining teriparatide with an antiresorptive agent have been proposed and studied. This article reviews the trial designs and the outcomes of combination therapies. Results of the combination therapy for teriparatide and bisphosphonates were mixed; while small increases of bone density were observed in the combination therapy of teriparatide and estrogen/SERM and that of teriparatide and denosumab. Those clinical studies were limited by small sample sizes and lack of fracture outcomes.

Leydig cell tumor in the post-menopausal woman: case report and literature review.

Leydig cell tumors of the ovary account for less than 0.1% of all ovarian tumors (1). We present two cases in which patients had markedly elevated serum testosterone levels and frank hirsutism. Both cases revealed right ovarian Leydig cell tumors upon oophorectomy with post-surgical resolution of hypertestosteronemia. While rare and difficult to diagnose, androgen secreting tumors should be suspected in women with hyperandrogenism and hirsutism, especially in the postmenopausal population.

Relative contribution of insulin sensitivity and beta-cell function to plasma glucose and insulin concentrations during the oral glucose tolerance test.

Plasma glucose and insulin concentrations have been used in genetic studies as quantitative phenotypic traits and also as surrogates for insulin sensitivity and beta-cell function. However, the significance of these traits in relation to insulin sensitivity and beta-cell function was unknown. We examined how insulin sensitivity and beta-cell function affected plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). This is a cross-sectional study enrolling 105 glucose-tolerant subjects (64 females; age, 18 to 40 years; body mass index, 17.58 to 37.57 kg/m(2); waist-to-hip ratio, 0.649 to 1.033 cm/cm). They participated in both OGTTs and hyperglycemic clamps. The relationship between plasma glucose and insulin concentrations and indices of insulin sensitivity and beta-cell function was examined. Univariate analyses showed that insulin sensitivity index (ISI) had some influence on plasma insulin concentrations (r(2) =.2623 to.3814) during the OGTT; however, it had only modest impacts on plasma glucose levels at 60, 90, and 120 minutes (r(2) =.0537 to.1300). Neither first phase (1stIR) nor second phase insulin response (2ndIR) affected plasma glucose concentrations. Multivariate analyses showed an independent impact (all P <.0001) of ISI on plasma glucose concentrations at 60, 90, and 120 minutes and on plasma insulin concentrations at every time point except at 30 minutes. Except for plasma insulin concentration at 30 minutes, of which 24% of the variation can be explained by 1stIR, beta-cell function (either 1stIR or 2ndIR) only had a very modest impact on 30-, 60-, 90- and 120-minute plasma glucose concentrations and on plasma insulin concentration at 60 minutes. In glucose-tolerant subjects, ISI plays an important role in determining postchallenged plasma glucose concentrations at 60, 90, and 120 minutes, as well as plasma insulin concentrations at fasting, 60, 90, and 120 minutes. However, beta-cell function is only reflected in plasma insulin concentration at 30 minutes through 1stIR. Therefore, we conclude that it is essential to measure beta-cell function in vivo if one plans to study the genetic influence of beta-cell dysfunction.

Virilization of a female infant by a maternal adrenocortical carcinoma.

OBJECTIVE: To describe a possible mechanism underlying the partial virilization of a 46, XX infant by a functional maternal adrenocortical carcinoma (ACC). METHODS: We performed immunocytochemical staining of tumor sections for luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptors. In addition, related reports in the literature are discussed. RESULTS: A previously healthy mother developed a large cortisol- and androgen-producing stage III adrenal tumor that did not interfere with conception or early morphogenesis. The tumor eluded detection until after delivery of a partially virilized 46, XX female infant with ambiguous genitalia. Immunohistochemical staining of tumor sections revealed overexpression of the LH/hCG receptor. Virilization of the genetically female fetus may have resulted from hCG-stimulated steroid secretion by the ACC. CONCLUSION: Because hypercortisolism and hyperandrogenism are associated with menstrual disturbances and spontaneous abortion, pregnancy in patients with functional adrenal tumors is uncommon. Rarely, maternal steroid excess from a functional adrenal tumor has caused 46, XX disordered sex differentiation. This unusual case demonstrates the influence of hCG on the functionality of an ACC and demonstrates the rare phenomenon of virilization of a female infant by a functional maternal adrenal tumor.

Novel treatment of medullary thyroid cancer.

PURPOSE OF REVIEW: Metastatic medullary thyroid cancer (MTC) is an incurable disease once metastasis becomes unresectable. Many therapeutic drugs and methods have been tried to circumvent this difficulty. We review currently published treatments and hope for future developments of more effective treatment methods. RECENT FINDINGS: Motesanib, vandetanib, axitinib (tyrosine kinase inhibitors), and XL184 (multikinase inhibitor) have been shown to achieve partial response or stable disease state of metastatic MTC. Sunitinib and sorafenib, currently available tyrosine kinase inhibitors, can also be tried for patients with MTC. However, these medications are not curative and do not improve survival rate. Only carcinoembryonic antigen-I-iodine-based radioimmunotherapy improved survival of a subset of patients with a very aggressive type of MTC. Drugs currently available for possible use of MTC treatment include bortezomib (proteasome inhibitor), valproic acid (histone deacetylase inhibitor), capecitabine (5-fluorouracil prodrug), and indomethacin (NSAID), although clinical studies have yet to be done. Cardiac natriuretic hormones and an extract of the plant Cautleya gracilis are new agents to be studied for MTC. SUMMARY: Kinase inhibitors are the first drugs showing some efficacy in MTC. To improve survival, unconventional drugs or other therapies with or without kinase inhibitors need to be considered.

Resection of thyroid cancer metastases to the sternum.

The role of surgical resection in patients with metastatic thyroid cancer is not clearly defined. Reported is a case of concurrent thyroid metastases to the lungs and sternum treated with total sternectomy followed by radioiodine therapy. A comprehensive review of the literature was also performed to evaluate the characteristics of reported cases of sternal thyroid cancer metastases treated with surgical resection. Overall, we demonstrate that radical resection of sternal metastases can be performed safely even in patients with poor prognosis to achieve palliation and potentiation of radioiodine therapy for concurrent metastases.

Economic benefits of intensive insulin therapy in critically Ill patients: the targeted insulin therapy to improve hospital outcomes (TRIUMPH) project.

OBJECTIVE: The purpose of this study was to analyze the economic outcomes of a clinical program implemented to achieve strict glycemic control with intensive insulin therapy in patients admitted to the intensive care unit (ICU). RESEARCH DESIGN AND METHODS: A difference-in-differences (quasi-experimental) study design was used to examine the associations of an intensive insulin therapy intervention with changes in hospital length of stay (ICU and total), costs (ICU and total), and mortality. Hospital administrative data were obtained for 6,719 adult patients admitted between 2003 and 2005 to one of five intervention or four comparison ICUs in a large academic medical center. Linear regression models with log transformations and appropriate retransformations were used to estimate length of stay (LOS) and costs; logistic regressions were used to estimate mortality. RESULTS: After adjustment for observable patient characteristics and secular time trends, the intervention was consistently associated with lower average glucose levels and a trend toward shorter LOS, lower costs, and lower mortality. However, associations with resource use and outcomes were statistically significant in only ICU LOS, with an average reduction of 1.19 days of ICU care per admission. Other associations, although large in magnitude and in the hypothesized directions, were not estimated with sufficient precision to rule out other net effects. The associations with ICU days and costs were larger in magnitude than total days and costs. CONCLUSIONS: A clinical team focused on hyperglycemia management for ICU patients can be a valuable investment with significant economic benefits for hospitals.

Verbal memory retrieval deficits associated with untreated hypothyroidism.

The effects of inadequate thyroid hormone availability to the brain on adult cognitive function are poorly understood. This study assessed the effects of hypothyroidism on cognitive function using a standard neuropsychological battery in 14 patients suffering from untreated hypothyroidism and complaining of subjective cognitive difficulties in comparison with 10 age-matched healthy comparison subjects. Significant differences between groups were limited to verbal memory retrieval as measured by the California Verbal Learning Test (CVLT). On short delay free recall, long delay free recall, and long delay cued recall, significant differences remained between groups despite the limited statistical power of this study. There were no significant results found between groups on attentional or nonverbal tasks. Results suggest that hypothyroid-related memory deficits are not attributable to an attentional deficit but rather to specific retrieval deficits.

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.

Comparison of the relationship of age and beta cell function in three ethnic groups.

DESIGN: Prevalence of type 2 diabetes and glucose intolerance increase with age. It has been demonstrated that beta cell function declines at about 1% per year in glucose tolerant Caucasians. However, this relationship is not known to exist in other ethnic groups. SUBJECTS AND MEASUREMENTS: We investigated the relationship of age to beta cell function (%B) and insulin sensitivity (%S), estimated by the homeostasis model assessment, in a nationally representative sample of healthy US adults who participated in a cross-sectional study, the third National Health and Nutrition Examination Survey. Only those subjects who had never been told to have diabetes by a physician, with HbA1C < 6% and fasting plasma glucose concentration < 5.56 mmol/l with proper fasting glucose and insulin concentration were included in this analysis (560 non-Hispanic whites, 231 non-Hispanic blacks and 298 Hispanics). RESULTS: Age was positively correlated to HbA1C and fasting glucose concentration, but it was negatively correlated to %B in all three ethnic groups. In contrast, ageing had no influence on %S in all three ethnic groups. Pair-wise comparison showed age had a similar influence among three ethnic groups on fasting glucose concentration, HbA1C and %B, respectively. Multivariate analysis confirmed an independent influence of age on fasting glucose concentration, HbA1C and %B among three ethnic groups. CONCLUSIONS: We observed %B declines at about 1% per year among all three ethnic groups. The age-related rising fasting plasma glucose concentration and HbA1C is most likely a consequence of age-related decline in beta cell function.

New insulin sensitivity adjusted beta cell indices: validation according to a genetic study.

PURPOSE: The role of hepatocyte nuclear factor-1alpha (HNF1alpha) in the maturity-onset diabetes of the young 3 (MODY3) is well established. A common polymorphism, I27L that is not linked to MODY3, has been demonstrated to affect beta cell function. To facilitate the identification of subjects with a low beta cell reserve, we developed beta cell indices and validated according to a genetic study. METHODS: Insulin sensitivity index (ISI), 1st phase insulin response (1stIR), and 2nd phase insulin response (2ndIR) were assessed in 60 glucose tolerant subjects using hyperglycemic clamps. Delta1stIR and delta2ndIR were defined as differences between 1stIR (or 2ndIR) and the ISI-adjusted 1stIR (or 2ndIR). The genotypes were determined from genomic DNA. RESULTS: Delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0482) differed among the 3 genotypic groups. Multivariate analysis confirmed the independent influence of the I27L polymorphism on delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0369). Within the LL group, 75% and 63% of the subjects were within the lowest quartile of delta1stIR (P = 0.0011) and delta2ndIR (P = 0.0277), respectively. CONCLUSIONS: With new beta cell indices, we demonstrated the independent impact of the I27L polymorphism on beta cell function. The new beta cell indices will facilitate the identification of glucose tolerant subjects with reduced beta cell reserve.

A parathyroid hormone-related protein-secreting metastatic epithelioid leiomyosarcoma. A case report and review of the literature.

A diagnosis of parathyroid hormone-related protein (PTH-rP)-secreting metastatic uterine epithelioid leiomyosarcoma was made in a 61-year-old woman with humoral hypercalcemia of malignancy. A primary uterine tumor had been removed 10 years previously, which had been associated with a short history of hypercalcemia. The original uterine tumor was diagnosed as a smooth muscle tumor of uncertain malignant potential. To the best of our knowledge, this is the first reported case of a PTH-rP-secreting uterine leiomyosarcoma. We demonstrate the dramatic changes in serum calcium, phosphorus, PTH, and PTH-rP levels after tumor resection. Extensive biochemical analysis and detailed immunohistochemical and ultrastructural characterization demonstrate several features of this tumor.