Autoimmunity and thyrotropin level in developing thyroid malignancy.

OBJECTIVE: Malignancies and autoimmune thyroid disease are still controversial, but recent studies prove that a long lasting thyroid disease may be linked with malignancy, e.g. papillary thyroid carcinoma in patients with Hashimoto thyroiditis. Having in mind that thyrotropin is a thyroid growth factor, the relationship between its serum values, as well as the levels of anti-peroxidase and anti-thyroglobulin antibodies and thyroid malignancy in patients with nodular thyroid goiter was examined. PATIENTS AND METHODS: Six-hundred-thirty-seven medical records, which included the thyroid fine-needle aspiration cytology were retrospectively evaluated. Patients were grouped regarding the levels of thyrotropin, anti-peroxidase and anti-thyroglobulin antibodies (in or out of the reference ranges) and compared with cytology findings for establishing their prognostic potential for malignancy. RESULTS: Elevated serum thyrotropin (≥ 4.5 mIU/L) was found in 27.3% of patients with thyroid malignancy compared with 10.8% with benign and 16.1% with unspecified cytology finding (p < 0.01). In the group of patients with malignant cytology findings 7.0% of them had elevated anti-peroxidase antibodies level, and 1.4% had anti-peroxidase antibodies level in reference range. In the group of patients with malignant cytology findings 4.2% of them had elevated anti-thyroglobulin antibodies level, and 1.4% had anti-thyroglobulin antibodies level in reference range. CONCLUSIONS: In patients with elevated serum thyrotropin concentration and/or chronic thyroiditis the occurrence of thyroid malignancy is increased.

Thyroid dysfunction and thyroid autoimmunity in euthyroid women in achieving fertility.

OBJECTIVE: Thyroid disease is the second most common endocrine condition in women of childbearing age. Thyroid hormones are involved in control of menstrual cycle and in achieving fertility affecting the actions of follicle-stimulating hormone and luteinizing hormone on steroid biosynthesis by specific triiodothyronine sites on oocytes; therefore, affect all aspects of reproduction. It remains controversial if pregnant women should be screened for thyroid dysfunction. Purpose of this review was to examine recent studies on the assessment of thyroid dysfunction in pregnancy, its treatment and newly perspective of thyroid autoimmunity in pregnant euthyroid women in achieving fertility. METHODS: An electronic search was conducted using the internet medical databases: Medline/PubMed, EMBASE, EBSCO, and the Cochrane library. RESULTS: Thyroid gland faces great challenge in pregnancy when many hormonal changes occur. Precondition for normal follicular development and ovulation is pulsate gonadothropin realizing hormone secretion. Thyroid dysfunction in pregnancy is classified as forms of hypothyroidism (positivity of thyroid autoantibody, isolated hypothyroidism, and subclinical or overt hypothyroidism), hyperthyroidism, and autoimmune disease, but also thyroid nodules and cancer, iodine insufficiency and postpartum thyroiditis. These conditions can cause adverse effects on mother and fetus including pregnancy loss, gestational hypertension, or pre-eclampsia, pre-term delivery, low birth weight, placental abruption and postpartum hemorrhage. There is an evidence that thyroid autoimmunity, in thyroid dysfunction adversely affects conception and pregnancy outcomes, but it is unclear what impact has isolated eumetabolic thyroid autoimmunity in achieving fertility, especially in women undergoing in vitro fertilization. Treatment of euthyroid pregnant women with positive thyroid peroxides antibodies is still controverse, but not few studies show that levothyroxine substitution is able to lower the chance of miscarriage and premature delivery. CONCLUSIONS: Further randomized trials are needed to expand our knowledge of physiologic changes in thyroid function during the pregnancy and to reveal mechanisms by which thyroid autoimmunity in euthyroid women affect fertility, especially the success of assisted reproductive technology in achieving the same and validity of levothyroxine administration in thyroid autoimmunity positive women.

Further studies on delineating thyroid-stimulating hormone (TSH) reference range.

The aim of the study was to evaluate thyroid-stimulating hormone (TSH) concentration in a reference group and to compare it with the TSH in subjects with high probability of thyroid dysfunction. The study population consisted of 852 subjects. The reference group consisting of 316 subjects was obtained by the exclusion of the subjects having thyroid disease, taking thyroid influencing drugs, having increased thyroid peroxidase (TPO) antibodies, or having abnormal thyroid ultrasound. 42 high probability of thyroid dysfunction subjects were defined by the association of increased TPO antibody concentration, changed echogenicity, and changed echosonographic structure of thyroid parenchyma. In the reference group TSH reference range was 0.45 mU/l (95% CI 0.39-0.56 mU/l) to 3.43 mU/l (95% CI 3.10-4.22 mU/l). To distinguish reference and high probability of thyroid dysfunction group a TSH threshold was calculated. At a threshold value of 3.09 mU/l (95% CI 2.93-3.38 mU/l), specificity was 95% and sensitivity 38.1%. Using 2 different approaches to find upper limit of the TSH reference range we obtained similar results. Using reference group only a value of 3.43 mU/l was obtained. Using both reference group and subjects with the high probability of thyroid dysfunction we obtained 95% CI for the upper reference limit between 2.93 and 3.38 mU/l. Based on these premises, it could be argued that conservative estimate of the TSH upper reference range should be 3.4 mU/l for both sexes.

Glucocorticoid effect on insulin sensitivity: a time frame.

It is well known that glucocorticoids induce insulin resistance, but the exact time scale in humans is not well known. The aim of the study was to determine the time scale of effects of pharmacologic doses of glucocorticoids on insulin sensitivity. Subjects were treated with repeated methylprednisolone infusions and oral prednisone for Graves' orbitopathy. Insulin sensitivity was determined using euglycemic hyperinsulinemic clamp (EHGC) before, during the first glucocorticoid infusion and after 2 months of treatment. EHGC started 2 h after the start of the glucocorticoid infusion, and lasted for 2 h. In another group of patients, insulin sensitivity was determined by short insulin tolerance test (SITT) before and during the first glucocorticoid infusion. SITT started 15 min after the start of the glucocorticoid infusion and lasted for 15 min. Ten subjects were included in each protocol. All were euthyroid during the study period. Four hours after the start of the glucocorticoid infusion significant reduction of insulin sensitivity was observed, which did not change for a further 2 months of glucocorticoid treatment [before 7.82 (95% confidence interval (CI) 5.35-10.29), first infusion, 4.93 (95% CI 2.99-6.87), after 2 months 5.36 (95%CI 3.91-6.81) mg/kg/min]. No significant change in insulin sensitivity occurred during the first 30 min of glucocorticoid infusion [before 139.7 (95%CI 94.1-185.3), during 146.7 (95%CI 106.3-187.1) mumol/l/min]. In humans, glucocorticoid- induced insulin resistance develops quickly, in about 4 h, and does not change during further glucocorticoid treatment.

Temporal coupling of luteinizing hormone and follicle stimulating hormone secretion in polycystic ovary syndrome.

The aim of this study was to assess the luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile secretion and their temporal relation (concordance) in subjects with polycystic ovary syndrome (PCOS). Fifteen subjects were included in the study (age 17-30 years, body mass index (BMI) 19.38-33.46 kg/m2). For the LH and FSH determinations, blood sampling started at 23.00 and lasted for 6 h with an intersample interval of 10 min. Pulse analysis was carried out using the PulsDetekt program. LH/FSH pulse concordance was calculated using the specific concordance index. Gonadotropin co-pulsatility was found in six subjects who were significantly younger than the others (median 18.5 vs. 22.5 years, p = 0.036). BMI, hirsutism grade, insulin sensitivity, estradiol, progesterone, testosterone, prolactin, cortisol and results obtained from the pulsatility analysis did not significantly differ between the groups. A serum cortisol concentration was correlated with the increased LH/FSH lag time (p = 0.851, p = 0.036) all subjects were included. In conclusion, two distinct LH/FSH secretory patterns were found in PCOS patients, manifested by the presence or absence of the concordance of gonadotropin secretion. In the group where LH/FSH co-pulsatility was present, correlation was found between the serum cortisol and the LH/FSH lag. We also confirmed the finding of previous studies that LH and FSH secretion are regulated by two different mechanisms.

[Treatment of Grave's ophthalmopathy with high doses of corticosteroids]. / Lecenje Grejvsove oftalmopatije visokim dozama kortikosteroidnih lekova.

UNLABELLED: Severe ophthalmopathy with sight impairment and double vision due to a compressive optic neuropathy, extraocular muscle thickness and corneal exposure occurs in 3-5% of all patients with Graves' hyperthyroidism [1]. Steroids are the choice of treatment for ophthalmopathy in more than 50%, and with orbital radiotherapy or surgical decompression in more than 70% of cases [2]. In severe ophthalmopathy steroids are effective in more than 60% of patients [1, 3], but to be effective high dosage is necessary [1, 4-6]. High-dose intravenous steroid pulse therapy is probably preferable to oral steroids giving a better response with fewer adverse effects [6]. The aim of the study was to evaluate the efficacy of high-dose intravenous methylprednisolone pulse therapy followed by oral steroids in the treatment of patients with severe Graves' ophthalmopathy. PATIENTS AND METHODS: Fourteen euthyroid patients with severe Graves' ophthalmopathy were treated with high-dose intravenous methylprednisolone during 6 months and followed-up for 24-48 months by clinical and ophthalmological assessment. During three days two doses of methylprednisolone were given as 500 mg in 500 ml isotonic saline infusion. The treatment was followed by oral prednisone 40 mg daily and tapered off to 10 mg in four weeks when next course of therapy started. There were no contraindications for steroid treatment. Characteristics of the group are presented in Table 1. Ophthalmological assessment relating to the status of cornea, extraocular muscles, eyelids, proptosis and optic nerve function was done during the study. It provides the measurement of visual acuity, intraocular pressure, visual evoked potentials, palpebral apertures and proptosis, fundoscopy, the assessment of ocular motility, visual fields, color vision, lagophthalmos and corneal changes. For better evaluation of eye disease clinical activity score and patients self-assessment were used. Thyroid hormones and thyroid microsomal antibodies were measured during the study. All patients were photographed before and after treatment. Orbital computed tomograms were performed before and after treatment for extraocular muscles assessment. Data were analyzed by Wilcoxon test. RESULTS: Clinical activity score fell significantly within the first week of therapy in all patients and remained stable during the follow-up period (before treatment: mediana 5, min 3, max 7 and after: mediana 2, min 1, max 4, p < 0.01). Proptosis (Table 2, Figure 1) was significantly reduced (mean values before and after treatment were 24.15 mm and 22.75 mm respectively, the difference was 1.40 mm; p = 0.014). Visual acuity was improved in 2 of 5 patients (Table 3). Ophthalmological assessment of color vision, fundal changes, visual fields and intraocular pressure is presented in Table 4. Five of 9 patients experienced loss or amelioration of diplopia after a 3-6 month treatment. The ocular motility was normalized or improved in 9 of 10 patients. The extraocular muscle enlargement on orbital CT scans decreased in 10 patients (mean score before and after treatment was 6.9 and 3.8 respectively). Minimal and transient side effects were observed during treatment. DISCUSSION: The best parameters of severity of the disease and of response to treatment are those related to assessment of optic nerve function, ocular motility and corneal status [6, 10]. In this series of 14 patients treated with high-dose steroids we found an improvement in visual acuity and color vision and normalization of visual fields, intraocular pressure, visual evoked potentials and fundal changes within a few days of treatment. Clinical activity score (CAS) was significantly and promptly reduced by therapy as most reports revealed [3, 5, 8]. CAS has a high predictive value for the outcome of treatment since it is based on signs of inflammation. The low score level, however, does not preclude a therapeutic success [9]. A mean value of proptosis was significantly reduced by thera

Effect of weight loss on the pulsatile insulin secretion.

The aim of the study was to assess whether pulsatile insulin secretion is variable in the same individual and is related to changes in insulin sensitivity. Insulin sensitivity and pulsatility were measured before and after weight reduction in nine obese subjects. A pulsatility analysis was done using the PulsDetekt program. Blood was sampled every 2 min over a period of 90 min. The secretion randomness was quantified using approximate entropy (ApEn), and ApEn normalized by SD of the insulin time series (nApEn). Lower values indicate more regular secretion. Insulin sensitivity was measured using the homeostasis model assessment. Data are presented as median, minimum-maximum. After weight loss insulin sensitivity was increased (12.16, 7.60-76.70 vs. 38.96, 19.88-74.96%), the number of insulin pulses was reduced (11, 8-16 vs. 9,6-12), and they were more regular (ApEn, 0.92, 0.53-133 vs. 0.69,0,40-1.27; nApEn, 1.07, 0.74-1.33 vs. 0.97, 0.54-1.42). Before and after the weight loss there was a correlation between ApEn and nApEn and insulin sensitivity. Therefore, insulin secretion regularity is variable in the same individual and is related to insulin sensitivity.

Effect of insulin sensitivity on pulsatile insulin secretion.

OBJECTIVE: The aim of the study was to determine whether derangements in insulin pulsatility are related to the presence of insulin resistance or whether these changes occur only in non-insulin-dependent diabetes mellitus (NIDDM). DESIGN AND METHODS: The study included 26 obese, 11 NIDDM and 10 control subjects. The obese group was divided into a low insulin (plasma insulin <20 mU/l, OLI, 14 subjects) and a high insulin (OHI, 12 subjects) group. For pulsatility analysis blood was sampled every 2 min for 90 min. Pulsatility analysis was carried out using the PulsDetekt program. The insulin secretion randomness was quantified using interpulse interval deviation (IpID) and approximate entropy (ApEn). ApEn and ApEn normalized by s.d. of the individual insulin time series (nApEn) were calculated. Lower values of ApEn and IpID indicate more regular secretion. Homeostasis model assessment (HOMA) was used to quantify insulin sensitivity. RESULTS: Insulin pulses were significantly less regular in the OHI and the NIDDM groups compared with the control and the OLI groups (control: ApEn 0.54+/-0.16, nApEn 0.69+/-0.19, IpID 2.53+/-0.99; OLI: ApEn 0.64+/-0.12, nApEn 0. 79+/-0.15, IpID 2.92+/-1.09; OHI: ApEn 0.88+/-0.07, nApEn 0.92+/-0. 07, IpID 3.95+/-0.84; NIDDM: ApEn 0.92+/-0.16, nApEn 0.99+/-0.09, IpID 4.41+/-0.53; means +/- s.d.). There was no difference in the pulse regularity between the OHI and the NIDDM groups. CONCLUSIONS: Decrease in insulin sensitivity was correlated with the reduction of insulin secretion regularity. Therefore irregular insulin secretion is related to a reduction in insulin sensitivity, and it is not unique to NIDDM.

[Anemia in hypothyroidism]. / Anemije u hipotireozi.

INTRODUCTION: Anemias are diagnosed in 20-60% patients with hypothyroidism. Real values of the degree of anemia are estimated by radioisotopic analysis due to the lower volume of plasma in hypothyroidism causing false high levels of hemoglobin in blood. Anemia is often the first sign of hypothyroidism. Diagnosis of hypothyroidism should be considered in every case of anemia with uncertain etiology because sometimes signs of overt hypothyroidism needn't necessarily be evident. Microcytic, macrocytic and normocytic are regularly described anemias. CLASSIFICATION: Microcytic anemia is usually ascribed to malabsorption of iron and loss of iron by menorrhagia. Macrocytic anemia is caused by malabsorption of vitamin B12, folic acid, pernicious anemia and inadequate nutrition. Pernicious anemia occurs 20 times more frequently in patients with hypothyroidism than generally. Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the thyroid hormones themselves without nutritive deficit. Normocytic anemia, so-called uncomplicated anemia, arises due to thyroid hormones deficit itself not followed by nutritive deficit. This type of anemia is considered to be an adaptation to a decreased basal metabolism. Thyroid hormones directly or indirectly, through erythropoietin, stimulate growth of erythroid colonies (BFU-E, CFU-E). Normocytic anemia is characterized by reticulopenia, hypoplasia of erythroid lineage, decreased level of erythropoietin, mainly regular erythrocyte survival. Acanthocytosis findings in cytologic blood smear suggest hypothyroidism in about 90% of cases.

Optimizing the diagnostic criteria for standard (250-microg) and low dose (1-microg) adrenocorticotropin tests in the assessment of adrenal function.

ACTH stimulation is the standard test for assessment of adrenal function. It was suggested that the low dose (1 microg) would be more sensitive for detecting mild secondary adrenal insufficiency than the usual dose of 250 microg. The aim of this study was to find the optimal diagnostic criteria and to compare standard dose test (SDT) with the low dose test (LDT). A group of patients treated with corticosteroids for the 6 months was considered to have hypothalamo-pituitary-adrenal impairment. Studies were performed in 14 corticosteroid-treated and 28 control subjects in random order on 2 consecutive days. Tests were analyzed using the receiver operating characteristic curve method. The best test was cortisol increment at 15 min of the LDT. It was significantly better than the cortisol concentration at 15 min of the SDT, the best test during the SDT (receiver operating characteristic curve area and 95% confidence interval: LDT, 0.997 and 0.956-0.999; SDT, 0.827 and 0.662-0.929; P = 0.0113). For the cortisol increment at 15 min of the LDT at 100% sensitivity, the diagnostic value was 100 mmol/L, and the specificity was 96%. Therefore, the LDT is superior to the standard dose test in the assessment of secondary adrenal insufficiency.

Influence of three-week fasting on gonadotropin pulsatility in obese menstruating women.

OBJECTIVE: To evaluate the influence of three-week fasting on gonadotropin pulsatility in extremely obese women of reproductive age. DESIGN: Prospective study of 21-day fasting (400 kcal/day), under medical supervision. SUBJECTS: 20 females, average age of 35.1 +/- 5.9 y, and average BMI of 41.19 +/- 8.39 kg/m2, with regular menstrual cycles (26-34 days). The mean weight loss was 12.5 +/- 3.23 kg. MEASUREMENTS: Blood samples for LH and FSH were taken between 4th and 7th day of the menstrual cycle, before and in the first cycle immediately after weight reduction, for 6 h, starting at 09.00 with 10 min intersample intervals. Pulsatility analysis was done using Pulsar program. Statistical analysis was done using Wilcoxon's matched pairs signed ranking test and McNemar's test. RESULTS: There was no statistically significant difference (p > 0.05) in LH and FSH pulsatile secretion before and after diet including the number of pulses, amplitudes, interpulse intervals and peak lengths. There were no disturbances of menstrual cycle during or after the diet. CONCLUSION: These results suggest that a 21-day fast, accompanied with significant weight loss, does not affect gonadotropin pulse pattern in follicular phase and normal menstrual cycle length in extremely obese females of reproductive age, compared with the pattern before diet.

[The effect of cilazapril and prazosin on insulin sensitivity in patients with essential hypertension]. / Uticaj cilazaprila i prazosina na insulinsku senzitivnost u bolesnika s esencijalnom hipertenzijom.

Two groups of drugs are actual for improving effects of insulin in vivo: alpha-1-adrenergic blockers and angiotensin-converting-enzyme-inhibitors. The objective of this study was to examine short-term effects of cilazapril and prazosin therapy on insulin sensitivity assessed by a 15' test of insulin tolerance of obese hypertensive persons. In groups of 8 patients insulin tolerance was tested prior to and 7 days after therapy by cilazapril dosed to 2.5 mg a day and prazosin 3 mean 1-2 mg a day. In this way satisfactory control of arterial tension was achieved. No significant changes of coefficient which enable assessment of insulin effects in vivo were established. However, in the group treated with cilazapril there were 6 out of 8 patients in whom coefficient increase was registered, so that among groups there was a significant difference in coefficient change in regard to therapy with better cilazapril effects.

[Diagnosis and monitoring of patients with type IIa multiple endocrine neoplasms]. / Dijagnostika i pracenje bolesnika s multiplom endokrinom neoplazijom tip IIa.

Syndrome of multiple endocrine neoplasia, type IIa, is a rare disturbance made by medullar carcinoma of the thyroid gland, pheochromacytoma and hyperparathyroidism. The article deals with three patients with multiple endocrine neoplasia, type IIa, with special emphasis to detection of the disease in time and treatment of the patients in the early phase of the illness. This is a hereditary autosomal dominant disturbance. Tests performed among members of family with high risk factors of the disease are of great importance. In this way early diagnosis is possible, and consequently, prevention of fatal issue due to pheochromocytoma and medullar carcinoma.

[Thyroiditis]. / Tireoiditis.

We reviewed the results of the long term study of incidence, clinical characteristics, some etiological possibilities and pathogenetic mechanisms in inflammatory diseases of thyroid gland. Among persons who suffered of acute thyroiditis we presented the most frequent causes and prominent clinical characteristics in the course of the disease with special interest for predisposing factors. Contrary to the most frequent opinions, the number of cases with subacute (de Quervain) thyroiditis is so similar to the number of cases with Graves diseases. For these reason we concluded that subacute thyroiditis is important medical problem, in spite of its benignity. Even well known clinical characteristics and therapy of subacute thyroiditis, etiology and pathogenetic mechanisms are not well estimated. The group of chronical thyroiditis described as autoimmune thyroiditis, indicates on etiology of this heterogeneous group of thyroid diseases. Modern aspects of therapy are shown at the end of the study.

[Determinants of susceptibility to the induction of autoimmune diabetes in inbred strains of rats]. / Ispitivanje determinanti ostljivosti na indukciju autoimunog dijabetesa u cistih sojeva pacova.

Interleukin 2 (IL 2) proved to be important for the generation of autoreactive T cells in the pathogenesis of different autoimmune disorders, including diabetes. Also, we have previously shown that lymphoid cells obtained from inbred strains of rats Dark August (DA) and Albino Oxford (AO) exhibited a genetically determined difference in their ability to produce IL 2. In this study, in DA and AO rats, we analysed the susceptibility to the induction of autoimmune diabetes with multiple subdiabetogenic doses of alloxan. Rats were injected i.v. with 25 mg/kg b.w. of alloxan in 5 consecutive days. All DA rats developed moderate and persistent hyperglycaemia 15 days after the induction. In contrast, AO rats failed to develop the disease after the same regimen of induction. When the induction was made in (AO x DA)F1 rats, all of them developed the disease similar to the susceptible parental DA strain. However, the onset was delayed (the 40th day after the induction) and the glycaemia was constantly lower than in DA rats. Our results indicate that the difference in the response to the induction of autoimmune diabetes between susceptible DA strain, being high IL 2 producer, and resistant AO strain, being low IL 2 producer, is genetically determined. The results also suggest that this control could involve the gene determining the level of IL 2 production in DA and AO rats, thus signifying that the susceptibility to the induction of this form of autoimmune diabetes could be related to the level of IL 2 activity.

Postprandial response of serum cationic trypsin-like immunoreactivity in insulin-dependent diabetes mellitus.

Conflicting reports exist on the postprandial response of serum cationic trypsin like immunoreactivity (SCTLI). The purpose of the current study was to examine the postprandial response of SCTLI in healthy persons and in insulin dependent diabetes mellitus (IDDM) patients and relate this to C-peptide secretion. The study was performed on six healthy males 25-40 years old and in nine male IDDM patients 25-38 years old. To all the patients after an overnight fast was given a standardized breakfast. Blood samples were obtained through a butterfly needle inserted into the antecubital vein at 0, 30, 60 and 120 minutes. Radioimmunoassays were performed using commercially available kits: for SCTLI CIS-SORIN and for C-peptide BIODATA. In healthy persons there was a significant rise of SCTLI concentration at 30 minutes, and C-peptide at 30 and 60 minutes. IDDM patients showed lower basal levels of SCTLI and C-peptide, without any significant changes of SCTLI and C-peptide during the test. We concluded that trypsin appearance in serum closely correlates with endocrine pancreatic function.