Spectral effect: each population must have its own normal midnight salivary cortisol reference values determined.

INTRODUCTION: The mesurement of midnight salivary cortisol provides the most sensitive method for screening of Cushing's sendrome. However the clinical significance of spectral error is the requirement for determination of normal reference values in each population for each test, which will be used as the diagnostic method. Salivary cortisol levels may be affected by individual factors such as nutrition, sleep, medication, activity, and gender. Being a non-invasive method, midnight salivary cortisol (MSC) has been used as a valuable indicator of free plasma cortisol. MATERIAL AND METHODS: Midnight salivary cortisol was assessed in randomly selected 100 Turkish patents who underwent to a detailed physical examination. Saliva samples were collected at 00:00 to plastic tubes with the help of plastic pipettes, without brushing their teeth, but after rinsing their mouth. Salivary cortisol was measured with luminescense immunoassay kit. Differences and correlations were analysed. RESULTS: The mean midnight salivary cortisol of the healthy population was 0.21 ±0.03 µg/dl. Body mass index, age, sex, smoking, exercise, educational status alcohol, had no effect on the MSC. CONCLUSIONS: Consequently, normal salivary cortisol reference ranges must be used for different assays and different populations in order to evaluate more accurately pituitary-adrenal axis pathology in clinical practice.

Prevalence of pituitary adenomas in macroprolactinemic patients may be higher than it is presumed.

One form of prolactin (PRL) is macroprolactin with high molecular mass. Many macroprolactinemic patients have no pituitary adenomas and no clinical symptoms of hyperprolactinemia, it is controversial whether macroprolactinemia is a benign condition that does not need further investigation and treatment. In this study, we aimed to compare macroprolactinemic patients (group I) with the true hyperprolactinemic patients (group II) for the presence of pituitary adenoma. We investigated 161 patients with hyperprolactinemia, whose magnetic resonance imaging records of the pituitary were taken. All patients were questioned for irregular menses, infertility and examined for galactorrhea. Patients were screened for macroprolactinemia by polyethylene glycol precipitation, and a recovery of ≤40% and normal monomeric PRL level was taken as an indication of significant macroprolactinemia. Of 161 patients with hyperprolactinemia, 60 (37.26%) had macroprolactinemia. PRL levels of group II were lower than those of group I (P = 0.011), although monomeric PRL levels of group II were higher than those of group I (P = 0.0005). Of 60 macroprolactinemic patients, 16 (26.7%) had pituitary adenomas. The prevalence of pituitary adenomas was lower in group I, compared with group II (P = 0.0005). No significant differences were found between the prevalences of irregular menses and infertility of group I and II (P = 0.084, P = 0.361). Prevalence of galactorrhea in group I was lower than that in group II (P = 0.048). Prevalence of pituitary adenomas in macroprolactinemic patients is lower compared with the true hyperprolactinemic patients, but may be higher than that found in other recent studies and in the general population.

Papillary thyroid carcinoma patients assessed to be at low or intermediary risk after primary treatment are at greater risk of long term recurrence if they are thyroglobulin antibody positive or do not have distinctly low thyroglobulin at initial assessment.

BACKGROUND: In papillary thyroid carcinoma (PTC), recurrences during long-term follow-up (R-LTFU) occur even in those who appear to have an excellent prognosis after initial thyroid surgery and usually, radioactive iodine (i.e., "primary treatment"). Initial studies that predict R-LTFU are not well defined. Values for serum thyroglobulin (Tg) measurements when serum thyrotropin (TSH) is >30 µU/mL, as a result of either recombinant TSH or L-thyroxine withdrawal, referred to here as stimulated Tg (STg), have been previously evaluated. The aim of the current study was to determine the parameters associated with R-LTFU in patients with PTC categorized as having low-risk disease 9 to 12 months after their primary treatment. METHODS: This was a retrospective study of 469 patients with PTC with a mean follow-up 5.8±3.9 years. Study patients had to have no uptake in the first postablative diagnostic (131)iodine whole body scan (WBS) performed 9-12 months after primary treatment, a normal cervical ultrasonography (C-US), and STg of <2 ng/mL if their test for antithyroglobulin antibody (anti-Tg) was negative. The first two criteria were required for patients with a positive anti-Tg test, and their nominal serum Tg concentrations were not analyzed. RESULTS: Twelve patients developed recurrences (2.6%) in cervical region. Greater tumor size, higher STg, and positive anti-Tg tests at initial evaluation were associated with greater R-LTFU. The recurrence rates were 1.5% (7/450) and 26% (5/19), respectively, in patients with negative and positive anti-Tg tests at initial evaluation. Recurrence-free survival was lower in the patients with initial lymph node metastases, positive anti-Tg tests, and STg of ≥0.3 ng/mL at the first postablative WBS (p=0.022, 0.001, 0.035, respectively, by log-rank test). Regression analysis in patients who were anti-Tg negative revealed that STg ≥0.3 ng/mL at this first WBS was the only parameter related to recurrence (p=0.031, odds ratio: 10.30, confidence interval: 1.23-83.3). CONCLUSION: Patients with PTC traditionally categorized as low risk during their first 9 to 12 months after primary treatment have a greater risk of R-LTFU if their postablative STg is ≥0.3 ng/mL, or they have positive anti-Tg, even at this early stage. Periodic C-US is important in these patients and should probably be more frequent in patients with PTC who have positive anti-Tg tests or STg ≥0.3 ng/mL in the first year after diagnosis.

Effects of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women in short term.

OBJECTIVE: Fibroblast growth factor 23 (FGF23), a phosphatonin, inhibits renal phosphate reabsorption and suppresses 1-α hydroxylase activity. Calcitriol stimulates FGF23 synthesis in bone. We aimed to determine the effect of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women and to compare the FGF23 concentrations of vitamin D-deficient patients with healthy subjects and patients with genetically determined hypophosphatemic rachitis. DESIGN AND METHODS: The study group was composed of vitamin D-deficient females (n=18, mean age 29.1 ± 9.9 years), vitamin D-sufficient healthy females (control group; n=19, mean age 28.5 ± 5.2 years), and patients with genetically determined hypophosphatemic rachitis (n=13, mean age 26.5 ± 15.1 years). The groups were compared for serum FGF23, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), calcium, phosphate, bone turnover markers, intact parathyroid hormone (PTH), and urinary excretion of calcium and phosphate. The vitamin D-deficient group was re-evaluated after a standard treatment regimen. RESULTS: Serum FGF23 concentrations were significantly lower in vitamin D-deficient patients than in vitamin D-sufficient women and hypophosphatemic rachitis group. Serum FGF23 and phosphate concentrations further decreased significantly during replacement of vitamin D (P<0.05). A significant negative correlation was evident between FGF23 and PTH before vitamin D replacement in the patients (r=-0.469, P<0.05). CONCLUSION: Decreased FGF23 concentrations, which further decline during vitamin D replacement therapy, may have favorable action on bone mineralization by counterregulatory effect on phosphate homeostasis. Lower 1,25(OH)2D concentrations at baseline and hypophosphatemia during treatment may have dominating effects on FGF23 concentrations in vitamin D deficiency, leading to decreased FGF23 concentrations at baseline and during replacement therapy.

The long term outcome of papillary thyroid carcinoma patients without primary central lymph node dissection: expected improvement of routine dissection.

BACKGROUND: We investigated central compartment recurrence (CCR) and mortality rate in patients with papillary thyroid carcinoma (PTC) who had no central lymph node dissection (CLND) at the time of primary operation. METHODS: The medical records of 343 patients who underwent operations for PTC between January 1988 and December 2002 with a mean postoperative follow-up period of 9 +/- 4 years, were reviewed. RESULTS: Twenty-two patients (6%) had locoregional recurrence. The lateral, central, or both compartments were involved in 16, 2, and 4 of 22 patients, respectively. The rate of CCR was 2% (6/343). Five (2%) patients died from PTC due to locoregional invasion (tracheal and esophageal invasion) in 3 patients and distant metastasis in 2 patients. Older age (>or=60), initial metastatic lateral cervical lymph nodes, size of primary tumor size >or=3 cm, microscopic extrathyroidial extension, and aggressive histologic subtypes (diffuse sclerosing, tall-cell, poorly differentiated) of PTC were risk factors for CCR and mortality (P = .0001). CONCLUSION: Initial CLND might be of value to prevent CCR and mortality in PTC patients with initial metastatic cervical lateral lymph nodes, older age (age >or=60), primary tumor size >or=3 cm, and agressive histopathologic features of PTC.

Parathyroid changes after high dose radioactive iodine in patients with thyroid cancer.

OBJECTIVE: The study aimed to investigate the effect of high dose radioactive iodine (RAI) on parathyroid function in patients with differentiated thyroid cancer. METHODS: Nineteen patients (8 men/11 women, age 46.5 +/- 13.2 years) undergoing RAI for thyroid remnant ablation were enrolled in the study. The biochemical parameters related to parathyroid function [serum calcium (Ca), phosphate (P), creatinine (Cr), alkaline phosphatase (ALP), intact parathyroid hormone (iPTH), urinary Ca, cAMP concentrations and the maximum tubular capacity for phosphate per unit volume of glomerular filtrate (TmP/GFR)] were evaluated at baseline and at the 1st, 3rd, 6th and 12th months of RAI administration. SPSS 15.0 was used for statistical analysis. RESULTS: For all patients, thyroid-stimulating hormone levels were >30 U/ml at baseline and <0.1 U/ml at the following visits. Serum iPTH levels were decreased significantly at the 6th month and reached basal levels at the 12th month (baseline vs. 6th p = 0.027, 1st vs. 6th p = 0.011, 3rd vs. 6th p = 0.047, 3rd vs. 12th p = 0.014, 6th vs. 12th p = 0.001). At the 6th month, P and TmP/GFR levels were higher (p = 0.036, 0.017, respectively), and urinary cAMP measurements were lower (p = 0.020) compared to those of the 1st month. No difference was detected concerning the other parameters. Serum Ca levels decreased below 2.1 mmol/l in several patients (n = 5 at 1st month, n = 4 at 3rd month, n = 8 at 6th month and n = 3 at 12th month) without clinical symptoms. CONCLUSIONS: The study indicated a transient decline in PTH levels at the 6th month following RAI therapy. Although this decrease did not cause symptoms in any of the present cases, this pattern might be important especially in individuals with diminished parathyroid background.

The risk factors for malignancy in surgically treated patients for Graves' disease, toxic multinodular goiter, and toxic adenoma.

BACKGROUND: The impact of age, gender, and coexisting cold nodules on the frequency of thyroid carcinoma in hyperthyroid patients in an endemic iodine-deficient region was investigated. METHODS: The medical records of 817 patients who underwent operations for Graves' disease (GD) (n= 342), toxic multinodular goiter (TMG) (n = 299), and toxic adenoma (TA) (n = 176) between January 1988 and April 2006 were reviewed. RESULTS: Cold nodules were found in 293 (36%) of the patients, and 524 (64%) patients had no cold nodules. The incidence of thyroid carcinoma was 6.5% (53/817).The frequency of carcinoma was 3.8% in GD, 6.4% in TMG, and 12% in TA. The frequency of carcinoma in older patients (>/=50 years) was significantly higher than in younger patients (10.2% vs 4.3%, P = .001). The presence of cold nodules significantly increased the frequency of carcinoma (13% vs 2.9%, P = .001). A tumor was discovered within a cold nodule in 45% of the patients with thyroid carcinoma. CONCLUSION: Cold nodules are frequent in hyperthyroid patients in endemic iodine-deficient regions. Older patients (>/=50 years) and cold nodules are significant risk factors for malignancy in patients with hyperthyroidism. Surgical treatment may be suitable for those particular patients if malignancy can not be excluded.

Two novel GALNT3 mutations in familial tumoral calcinosis.

Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like glycosyltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroblast growth factor-23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low-normal serum concentrations of intact biologically active FGF23 and high levels of C-terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.

Clodronic acid in the treatment of postmenopausal osteoporosis.

BACKGROUND: Clodronic acid, a first-generation bisphosphonate, has been successfully used in the treatment of high bone turnover states, Paget's disease and osteolytic bone metastases. However, controversies remain over its optimal dosage and method of administration in the treatment of postmenopausal osteoporosis. In this study we aimed to evaluate the effect of clodronic acid treatment for 3 years on bone mineral density (BMD) in women with postmenopausal osteoporosis. METHODS: This was a prospective, open-label, randomised, controlled study that was conducted in an outpatient clinic at the Bone Metabolism Unit of a tertiary referral centre university hospital. Thirty postmenopausal women (age range 48-73 years) with osteoporosis and a control group of 49 osteoporotic women (age range 47-74 years) received randomised therapy. The clodronic acid group of participants received oral doses of clodronic acid 800 mg plus elemental calcium 500 mg and 400 IU of vitamin D daily, while the control group was treated with calcium and vitamin D only. BMD was measured by dual energy x-ray absorptiometry at yearly intervals. Biochemical markers of bone turnover were also measured. RESULTS: In this clinical study of postmenopausal women with osteoporosis, 36 months of clodronic acid treatment significantly increased average femoral neck BMD by 3.2 +/- 2.9%, trochanter BMD by 2.2 +/- 2.9% and lumbar spine BMD by 3.1 +/- 3%. In the control group, femoral neck, trochanter and lumbar spine BMD decreased by -6 +/- 2.7%, -7.3 +/- 2.5% and -5.4 +/- 2%, respectively (p<0.01, p<0.05 and p<0.05 for clodronic acid vs control, respectively). There was a significant decrease in urinary hydroxyproline (-38.3%) over 3 years in the clodronic acid group compared with baseline (p<0.05), while no significant change occurred in the control group. Clodronic acid was well tolerated and compliance was good. There were no clinically meaningful differences in the incidence of individual adverse events between the groups. CONCLUSION: These results indicate that daily oral administration of clodronic acid 800 mg provides benefits to skeletal bone density in osteoporotic postmenopausal women. Calcium and vitamin D supplementation alone did not prevent further bone loss.

Multiple cutaneous neuromas and macular amyloidosis associated with medullary thyroid carcinoma.

Multiple cutaneous neuromas are rarely seen in dermatology practice. We report a case of multiple cutaneous neuromas, macular amyloidosis (MA), and medullary thyroid carcinoma (MTC) and discuss the interrelationship of the associated conditions. Multiple endocrine neoplasia 2 (MEN 2) is a hereditary syndrome that comprises MEN 2A, MEN 2B, and familial MTC. Germline mutations in the RET proto-oncogene is the underlying cause of the syndrome. MEN 2A and MEN 2B show some common endocrine manifestations including MTC and pheochromocytoma. There are reports of families with MA and MEN 2A. Multiple mucosal neuromas occur in 100% of patients with MEN 2B syndrome. Cutaneous neuromas are infrequently reported in MEN 2B syndrome. Our patient was a heterozygote carrier of GAG-->GAC mutation (Glu 768 Asp) in exon 13, codon 768 of the RET proto-oncogene. We speculate that our patient may represent an unusual presentation of MEN 2B or an overlap of MEN 2A and MEN 2B syndromes or a sporadic MTC case with unusual associations.

The advantage of total thyroidectomy to avoid reoperation for incidental thyroid cancer in multinodular goiter.

HYPOTHESIS: To investigate the impact of total thyroidectomy on the rate of completion thyroidectomy for incidentally found thyroid cancer in euthyroid multinodular goiter. DESIGN: A randomized, prospective clinical trial. SETTING: A tertiary referral center. PATIENTS: Patients with euthyroid multinodular goiter without any preoperative suspicion of malignancy, history of familial thyroid cancer, or previous exposure to radiation were randomized (according to a random table) to total or near-total thyroidectomy leaving no remnant tissue or less than 1 g (group 1; n = 109) or bilateral subtotal thyroidectomy leaving 5 g or more of remnant tissue (group 2; n = 109). Patients with preoperative or perioperative suspicion of malignancy were excluded. MAIN OUTCOME MEASURES: We compared the complication rates and the incidence of thyroid cancer requiring radioactive iodine ablation and completion thyroidectomy between groups. RESULTS: There were no permanent complications. The rates of temporary unilateral vocal cord dysfunction and hypoparathyroidism showed no significant difference between groups 1 and 2 (0.9% vs 0.9% and 1.8% vs 0.9%, respectively; P>.05). Papillary cancer was found in 10 group 1 patients (9.2%) and 8 group 2 patients (7.3%) (P =.80). Of the 9 patients requiring radioactive iodine ablation, reoperation was avoided in 5 group 1 patients; the remaining 4 group 2 patients underwent completion thyroidectomy (P =.007). CONCLUSION: We recommend total or near-total thyroidectomy in multinodular goiter to eliminate the necessity for early completion thyroidectomy in case of a final diagnosis of thyroid cancer.

Acute renal failure associated with nonfulminant hepatitis A virus infection.

Hepatitis A is usually a mild self-limiting infection of the liver. Nonfulminant acute renal failure very rarely complicates type A viral hepatitis. An unusual case, a 32-year-old female with serologically proven acute hepatitis A infection, was complicated by acute renal failure and the patient in this study is the first case associated with Cushing's disease. She recovered, and the laboratory tests returned normal one month after initial hospitalization. Although the mechanism responsible for renal failure in acute hepatitis A virus infection is still uncertain, possible causes are discussed with the review of literature.