The effect of hypothyroidism on color contrast sensitivity: a prospective study.

BACKGROUND: Thyroid hormone has been shown to control retinal cone opsin expression, the protein of color vision, in adult rodents. OBJECTIVES: The aim of this study was to evaluate the effect of hypothyroidism on color contrast sensitivity in adult overt hypothyroid patients. METHODS: Thirty-eight overt hypothyroid (31 females, 7 males) subjects and 20 euthyroid (16 females, 4 males) controls were studied prospectively. Color vision examination was performed by Chromatest, a software program analyzing the tritan (blue-yellow) color contrast threshold (tritan CCT) and protan (red-green) color contrast threshold (protan CCT). Color contrast sensitivity analyses of hypothyroid subjects were performed on admission and after L-thyroxine treatment when biochemical euthyroidism was achieved. RESULTS: After a median period of 90 (90-210) days, 24 (19 females, 5 males) patients were euthyroid and eligible for a second color vision examination. Baseline tritan CCT and protan CCT values were significantly higher in the hypothyroid group compared to euthyroid controls, which clinically translates into impaired color contrast sensitivity (p < 0.001 and p < 0.001, respectively). There was a significant decrease in tritan CCT (p = 0.002) and protan CCT (p < 0.001) values in the hypothyroid group after euthyroidism was achieved, which denotes improvement in color contrast sensitivity. CONCLUSIONS: It is a novel finding of the current study that color contrast sensitivity is impaired in hypothyroidism and significantly improves after euthyroidism is achieved.

Coexistence of THRB and TBG gene mutations in a Turkish family.

OBJECTIVE: Resistance to thyroid hormone is a syndrome characterized by high serum free T4 levels and unsuppressed serum TSH concentration. Thyroxine-binding globulin complete deficiency manifests with low serum total T4 and T3 levels and normal serum TSH concentration. Our objective is to describe a family with the coexistence of resistance to thyroid hormone and thyroxine-binding globulin complete deficiency. METHODS: We conducted clinical studies and genetic analyses. RESULTS: The proband presented with mental retardation, hearing loss, and recurrent upper respiratory tract infections accompanied by high serum levels of TSH, T3, T4, and high thyroglobulin antibody titers. His elder sister presented with normal TSH and T3 and high serum T4 levels. Both patients were found to be heterozygous for the mutation P453A in the thyroid hormone receptor beta (THRB) gene. One of the proband's brothers had low serum total T3 and T4 and normal TSH concentrations, without any clinical manifestations. He was hemizygous for the mutation P50fs51X in the TBG gene. The proband's mother showed slightly elevated TSH, normal total T3 and T4, and elevated titers of thyroperoxidase antibodies and thyroglobulin antibodies. She was heterozygous for both THRB and TBG genes mutations. CONCLUSIONS: To our knowledge, this is the first report of the coexistence of THRB and TBG gene mutations in the same individual (mother of the proband), whereas other affected family members had only 1 of the 2 genes mutated. The case illustrates the difficulty that might be encountered in the interpretation of thyroid function tests when different genetic defects affecting thyroid function coexist.

Thyroid lipomatosis.

Thyroid lipomatosis is a rare condition characterized by the presence of abundant mature adipose tissue in the thyroid gland. We herein report the case of a 43-year-old man with chronic renal failure caused by amyloidosis presenting with an asymmetrically enlarging thyroid gland. The patient's thyroid hormone levels were normal, and test results for thyroid autoantibodies were negative. A thyroid scan showed diffuse uptake of the radioisotope with a cold area in the left lobe. The pathology of the thyroidectomy material indicated thyroid lipomatosis, and minimal amyloid staining was noted around the thyroid follicles. Thyroid lipomatosis should therefore be kept in mind when making a differential diagnosis of fatty infiltration of amyloid goiter.

Serum CXCL10 levels and neuromuscular manifestations in patients with autoimmune thyroid diseases.

OBJECTIVE: Serum C-X-C motif chemokine 10 (CXCL10) levels have been shown to be elevated in autoimmune thyroid diseases (AITD). This study sought to determine whether newly diagnosed AITD patients with neuromuscular findings had higher levels of CXCL10 than those without neuromuscular manifestations. DESIGN: A total of 80 patients were recruited to the study, which included treatment-naive hypothyroid Hashimoto's thyroiditis (n = 19) and hyperthyroid Graves' disease (GD; n = 21), euthyroid thyroid autoantibody-positive (n = 20) and -negative (n = 20) patients. METHODS: All patients underwent a thorough sensorimotor and neuromuscular examination. Serum samples were kept in - 20°C for further CXCL10 measurements with ELISA. RESULTS: There was a significant difference with regard to serum CXCL10 levels only between GD and euthyroid thyroid autoantibody-negative patient groups [187(12-418) vs. 37.5(2-542) pg/ml, p < 0.05]. However, a comparison of newly diagnosed AITD patients with and without neuromuscular manifestations in terms of serum CXCL10 levels yielded no significant difference. When a correlation of existence of a neuromuscular manifestation and serum CXCL10 levels was evaluated, a significantly positive correlation was noted between carpal tunnel syndrome (CTS) and serum CXCL10 levels [207 (95-748) pg/ml in CTS-positive vs. 117 (2-977) pg/ml in CTS-negative patients, p < 0.05]. CONCLUSIONS: In this study, from a number of neuromuscular manifestations, only the existence of CTS correlated with significantly higher CXCL10 levels in the whole study group. Further studies with larger numbers of patients with autoimmune-based hyper- and hypothyroidism may better clarify the hypothesis regarding a relationship between serum CXCL10 levels and neuromuscular manifestations of AITD.

The molecular pathogenesis and management of bronchial carcinoids.

INTRODUCTION: In terms of well-differentiated neuroendocrine tumors (NETs), the lung is the second most common site of occurrence, after the gastro-entero-pancreatic axis, and comprises ∼ 25% of all NETs which may occur in various parts of the body. Pulmonary NETs are classified into four groups including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma and large cell neuroendocrine carcinomas. Among pulmonary NETs, typical and atypical carcinoid tumors of the lung are generally indolent, but do have a (albeit low) potential to metastasize. AREAS COVERED: The molecular biology and novel molecular pathways and drug targets in bronchial carcinoids are reviewed in this paper. A full data search is performed through PubMed over the years 2000 - 2010 with key words 'neuroendocrine tumors of the lung, bronchial carcinoid, lung carcinoid, foregut carcinoid, pulmonary carcinoid, pulmonary NETs, lung NETs, molecular biology, autoradiography, nuclear medicine, treatment'; all relevant publications are included, together with selected publications prior to that date. EXPERT OPINION: Although lying at the benign end of the spectrum of pulmonary NETs, bronchial carcinoids can metastasize, and the pathogenesis of these tumors is poorly understood. Several intracellular signaling pathways are under investigation to define new targets for the successful treatment of these tumors. In terms of treatment, further research should additionally focus on the already known but promising drug options.

Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways.

Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

Significant hyperkalemia and hyponatremia secondary to telmisartan/hydrochlorothiazide treatment.

The renin-angiotensin-aldosterone system (RAAS) has crucial importance in maintaining blood pressure; thus blockade of RAAS is an effective antihypertensive treatment choice. The final step in RAAS stimulation is aldosterone secretion by angiotensin II, which leads to increased renal tubular sodium absorption and potassium secretion. Angiotensin II receptor blockers (ARBs) allow blockade of RAAS by blocking binding of angiotensin II to the AT(1) receptors. There are several fixed-dose combinations of ARBs with hydrochlorothiazide in the market, providing antihypertensive therapies with complimentary mechanisms of action. With such combinations, while ARB inhibits the vasoconstricting action and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and directly increases excretion of sodium and chloride in the distal tubule, and promotes water excretion. Also, hypokalemia, which may be triggered by increased urinary potassium loss induced by hydrochlorothiazide, is opposed by ARB use and hence ARB/hydrochlorothiazide combination is known to be safe in terms of potassium imbalance. In this case report, significant hyperkalemia and hyponatremia related to telmisartan/hydrochlorothiazide use in a diabetic patient has been presented.

Hashitoxicosis (or Graves' disease?) with pericardial effusion.

Regarding the letter to the Editor entitled "Hashitoxicosis with pericardial effusion" (published online in April 2009); a case with subclinical thyrotoxicosis has been diagnosed as Hashitoxicosis depending on the ultrasonographic thyroid echo pattern and positive thyroid autoantibodies. The validity of this diagnosis and probability of Graves' disease in this case has been discussed.

Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis.

BACKGROUND: Pituitary adenomas are common intracranial neoplasms, comprising 10 - 15% of all brain tumors. Data from autopsy studies suggest that pituitary adenomas develop in 17 - 25% of the population. Nevertheless, the pathogenesis of sporadic pituitary tumors still remains obscure. OBJECTIVE: In this review, the roles of MAPK (mainly Ras/extracellular signal-regulated protein kinase (ERK)) and PI3K/Akt signaling pathways in pituitary tumorigenesis are summarised. METHODS: A full data search was performed through PubMed over the years 2000 - 2009 with key words 'pituitary, pituitary tumor, molecular biology, Akt, MAPK, PI3K, ERK', and all relevant publications have been included, together with selected publications prior to that date. Growth factor receptor mutations and overexpression, G protein mutations, other signaling pathway abnormalities or genetic syndromes associated with pituitary tumors are not discussed as these topics are behind the scope of this review. CONCLUSIONS: There are preclinical data and human pituitary tumor studies that are compatible with increased Ras/ERK and/or PI3K/Akt pathway activity in pituitary tumors. Future research focusing on scaffold proteins and signaling modulators regulating these pathways may help identify the initiating transforming events and accordingly new strategies may be developed targeting these pathways in pituitary tumors.

Thyroid hemiagenesis with Graves' disease, Graves' ophthalmopathy and multinodular goiter.

Thyroid hemiagenesis is a rare congenital anomaly in which one of the thyroid lobes with or without isthmus fails to develop. Here we present a woman patient with thyroid hemiagenesis, Graves' disease and ophthalmopathy with nodular goiter. Fine needle aspiration biopsy of the dominant nodule was suspicious of malignancy. The patient was referred for surgery for total thyroidectomy. Histopathological examination of the surgical material revealed benign features. The present case confirms that, although rare, a number of concomitant thyroid disorders can exist in a single patient with thyroid hemiagenesis just as it is seen for a normally developed thyroid gland.

Medullary thyroid cancer: molecular biology and novel molecular therapies.

Medullary thyroid cancer (MTC) arises from neural-crest-derived parafollicular C cells of the thyroid gland and accounts for approximately 4% of all thyroid cancers. Up to 25-30% of MTC cases occur as inherited disorders while the remaining cases represent the sporadic form of the disease. In this review, the structure and signalling properties of the RET proto-oncogene in its wild-type and mutant forms, and its role in hereditary and sporadic MTC, are discussed. A full data search was performed through PubMed over the years 2000-2008 with the key words 'medullary thyroid cancer, treatment, molecular biology, RET, molecular mechanism', and all relevant publications have been included, together with selected publications prior to that date. We also review novel therapies for metastatic MTC, especially the tyrosine kinase inhibitors which have activity at multiple receptor subtypes, and summarize the current ongoing trials in this area. While such tyrosine kinase inhibitors, particularly those affecting RET activity such as vandetanib, sorafenib and sunitinib, are promising, the low rate of partial responses and absence of complete responses in all of the various trials of monotherapy emphasize the need for new and more effective single agents or combinations of therapeutic agents with acceptable toxicity.

Incidental thyroid carcinoma in thyrotoxic patients treated by surgery.

BACKGROUND AND AIMS: Thyroid malignancy detected incidentally in patients who are operated for thyrotoxicosis has been reported at different rates. The aim of this study was to investigate the rate of incidental thyroid carcinoma in thyrotoxic patients managed with surgery in our institution. METHODS: Of the 375 thyrotoxic patients who had thyroid surgery between the years of 1997-2004, 70.7% were females and 29.3% were males. Among thyrotoxic patients 65.3% (n=245) had toxic multinodular goiter (TMG), 16.8% (n=63) had toxic adenoma (TA) and 17.9% (n=67) had Graves' disease. RESULTS: Twenty-six (6.9%) of all thyrotoxic patients had thyroid carcinoma. Eighteen (7.3%) of TMG, 4 (6.3%) of TA and 4 (6%) of Graves' disease patients had thyroid carcinoma. Histologic examination revealed 18 papillary (9 microscopic), 5 follicular, 2 hurthle cell and 1 anaplastic carcinoma. CONCLUSION: In our study, incidental thyroid carcinoma was found in 6.9% of subjects with thyrotoxicosis. Papillary thyroid microcarcinomas constituted 34.6% (26/9) of these newly diagnosed thyroid carcinomas. The incidence of thyroid carcinoma was not higher in subjects with Graves' disease compared to TMG and TA. The rate of incidental thyroid carcinoma in subjects with thyrotoxicosis treated with surgery was similar to previous studies reported from different countries.

Euthyroid Graves' ophthalmopathy with negative autoantibodies.

Graves' disease is an autoimmune-based hyperthyroidism in which a number of different antibodies directed against thyroid tissue plays a role. Graves' ophthalmopathy is thought to be a consequence of this autoimmune basis and occurs in some patients with Graves' disease. On occasional cases, the disease may present only with ophthalmopathy without hyperthyroidism. A 32-year-old woman with euthyroid Graves' ophthalmopathy and negative thyroid autoantibodies, including TSH receptor antibody, is presented here.

Leptin response to oral glucose tolerance test in obese and nonobese premenopausal women.

The objective of this study was to investigate the serum leptin response to oral glucose stimulation in a group of obese and nonobese normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese (BMI: 37.7 +/- 6.3 kg/m2) and 14 nonbese (BMI: 21.5 +/- 1.0 kg/m2) age-matched, healthy premenopausal women were included in the study. Serum glucose, insulin, and leptin levels were measured at 30 min intervals during the 120 min of an oral glucose tolerance test (OGTT). Mean serum glucose, insulin, and leptin levels were significantly higher in the obese group compared to nonobese subjects during OGTT. Except for a 120 min decrement noted in obese women, no changes occurred in serum leptin levels during oral glucose stimulation in both groups. As a conclusion, absence of a significant elevation in serum leptin levels during OGTT in our obese subjects compared to nonobese subjects may be related to their normal metabolic variables despite being abdominally obese and insulin resistant.