Efficacy and safety of combined parenteral and oral steroid therapy in Graves' orbitopathy.

OBJECTIVE: Glucocorticoids (GC) are the treatment of choice for moderate-to-severe and active Graves' orbitopathy (GO), but optimal treatment is still . The aim of the present study was to analyze the efficacy and tolerability of combined parenteral GC pulse therapy followed by oral GC in the interpulse period. DESIGN: The study included 50 patients (48 ± 10 years; 37 female) with untreated, active and moderate-to-severe GO. Patients received 500 mg of methylprednisolone in 500 ml of physiologic saline. Infusion was repeated after 48 h and then followed by tapering doses of oral prednisone and the cycle repeated each month for the next 5 months. The cumulative dose was 10.2g.Ophthalmic assessment was performed before and 6 months after start of treatment. Side effects of GC therapy were evaluated and recorded each month. RESULTS: GC showed the greatest effectiveness on soft tissue changes (incorporated in the CAS). Median CAS values decreased from 4.5 to 2 (p>0.001). Improvement was demonstrated in 37 patients (74%), there was no change in 13 patients (26%) and none of the patients presented with deterioration of inflammatory status. Diplopia improved in 21 patients (42%), was unchanged in 28 patients (56%) and deteriorated in 1 patient (2%). Improvement in visual acuity occurred in 36% of patients. At 6 months, 33/50 patients (66%) demonstrated overall treatment response. Response to GC therapy was influenced by CAS, TSHRAb and smoking behavior. The only independent parameter associated with positive treatment response was CAS ≥ 4 (p<0.001). Side effects occurred in 35/50 patients (70%) and the vast majority of them were mild to moderate. During the 6-months follow-up period, 2/33 patients (6%) had relapsing GO. CONCLUSION: With appropriate selection of patients and careful monitoring during and after treatment, combined parenteral and oral GC therapy is effective and safe.

Left and right ventricular structure and function in subclinical hypothyroidism: the effects of one-year levothyroxine treatment.

BACKGROUND: The aim of this study was to investigate left ventricular (LV) and right ventricular (RV) structure, function, and mechanics in patients with subclinical hypothyroidism (SHT), and to evaluate the effect of a 1-year levothyroxine treatment. MATERIAL AND METHODS: We compared 45 untreated women with subclinical hypothyroidism and 35 healthy control women matched by age. All the subjects underwent laboratory analyses, which included a thyroid hormone levels (free T3, free T4, and TSH) test, and a complete 2-dimensional echocardiographic study. All the SHT patients received levothyroxine therapy and were followed for a year after euthyroid state was achieved. RESULTS: The LV mass index in the SHT participants before and after replacement therapy was significantly higher than in controls. In the SHT patients before the treatment, LV diastolic function and global function estimated by the Tei index were significantly impaired, whereas the LV systolic function was decreased. The results show that LV mechanics was significantly impaired in the SHT patients at baseline. Additionally, the SHT participants before levothyroxine substitution had increased RV wall thickness and significantly impaired RV diastolic and global function in comparison with the controls or the SHT subjects after the treatment. Furthermore, RV mechanics was also significantly deteriorated in the SHT patients before the treatment. CONCLUSIONS: Subclinical hypothyroidism significantly affected LV and RV structure, systolic, diastolic and global function, and LV and RV mechanics. Levothyroxine replacement therapy significantly improved cardiac structure, function, and mechanics in the SHT patients.

[Diabetes mellitus as a cause of sudden natural death--case report].

INTRODUCTION: Forensic medicine may face a serious problem when solving the death cause associated with disorders in glucose metabolism, especially in cases when dying due to diabetes mellitus is characterized as unclear natural death. CASE REPORT: In this article the authors present a case of sudden death of a 31-year-old male, allegedly an active healthy sportsman. On the basis of microscopical findings (hyalinisation of arterioles, vacuolisation of nuclei of hepatocytes, nodular intercapillar glomerulosclerosis as characteristic diabetic change of kidney, and diffuse myocardial fibrosis) it was concluded that this person had suffered from unrevealed diabetes mellitus that caused an early onset of atherosclerotic microangiopathy and chronic ischaemic heart disease leading to sudden death probably due to fatal arrhythmia (electrical cardiac death). CONCLUSION: In this particular case diabetes mellitus was unexpectedly suspected only because of the changes detected by the microscopic examination. Therefore, a possible fatal influence of diabetic hyperglycemia or hypoglycemia could not be excluded on the basis of the applied diagnostic procedures.

Cortisol response to ACTH stimulation correlates with blood interleukin 6 concentration in healthy humans.

OBJECTIVE: Interleukin 6 (IL6) has the ability to influence each level of the hypothalamo-pituitary-adrenocortical (HPA) axis. The aim of the study was to test whether IL6 concentration correlates with the adrenal cortex response to ACTH in healthy humans. We postulated that higher basal IL6 concentration would be associated with the higher cortisol response to the stimulation. DESIGN AND METHODS: Basal IL6 concentration was measured and a low dose (1 microg) ACTH test was performed to assess cortisol response. Twenty-seven apparently healthy subjects (11 male, 16 female, mean age 31.1 years, age range 22-47 years) were included in the study. RESULTS: Data are presented as mean+/-S.E.M. Basal IL6 level was 0.84+/-0.10 pg/ml. Basal cortisol was 351.9+/-18.3 nmol/l. Maximal cortisol during synacthen test was 653.0+/-20.6 nmol/l. Maximal cortisol increment was 301.1+/-20.0 nmol/l. IL6 concentration was not correlated with basal or maximal cortisol concentration, but correlated significantly with cortisol increment (r=0.63, 95% confidence interval) 0.42-0.83). CONCLUSIONS: In our study, we found that higher basal IL6 concentration is associated with the higher cortisol response to ACTH stimulation. Based on previous research and our data, IL6, even in low concentrations and under physiologic conditions, modulates adrenal cortex responsivity to ACTH. Therefore, it seems that immune modulation of HPA axis is also present under physiologic and not only pathologic conditions.

[The effects of three-week fasting diet on blood pressure, lipid profile and glucoregulation in extremely obese patients].

INTRODUCTION: Obesity is often accompanied by a number of complications including diabetes mellitus and cardiovascular diseases. Elevated blood pressure and lipids, as well as deterioration of glucoregulation are attributed, as the most significant factors, to development of diabetes mellitus and cardiovascular complications in obese patients. OBJECTIVE: The aim of our study was to evaluate the effects of a fasting diet on blood pressure, lipid profile and glucoregulatory parameters. METHOD: We included 110 patients (33 male and 77 female; mean age 35 +/- 1 years, body weight 131.7 +/- 2.6 kg, body mass index 45.4 +/- 0.8 kg/m2) who were hospitalized for three weeks for the treatment of extreme obesity with the fasting diet. At the beginning, during, and at the end of this period, we evaluated changes in blood pressure, lipid profile, as well as parameters of glucoregulation including glycaemia, insulinaemia, and insulin sensitivity by HOMA. Oral glucose tolerance test (OGTT) was performed in all patients at the beginning and at the end of the fasting diet. RESULTS: During the fasting diet, the body weight decreased from 131.7 +/- 2.6 kg to 117.7 +/- 2.4 kg (p < 0.001), the body mass index decreased from 45.4 +/- 0.8 kg/m2 to 40.8 +/- 0.8 kg/m2 (p < 0.001), and both systolic and diastolic blood pressure significantly declined (143 +/- 2 vs. 132 +/- 2 mm Hg, p < 0.001; 92 +/- 2 vs. 85 +/- 2 mm Hg, p < 0.001). In addition, the fasting diet produced a significant decrease in total cholesterol, LDL cholesterol, triglycerides, as well as basal glycaemia and insulinaemia (p < 0.001) Before the fasting diet, OGTT was normal in 76% of patients, whereas 21% of patients showed glucose intolerance, and 4% of patients diabetes mellitus. After the fasting diet, OGTT was normal in 88% of patients, whereas 12% of patients still had signs of glucose intolerance (p < 0.05). In addition, insulin resistance significantly (p < 0.05) increased from 54 +/- 6% to 89 +/- 13% after the fasting diet. CONCLUSION: The three-week fasting diet in extremely obese patients produced a significant decrease and normalization of blood pressure, decrease in lipids, and improvement in glucoregulation including the increase in insulin sensitivity.

[Autoimmune thyroid disease--clinical symptoms of associated autoimmunity].

Autoimmune diseases are manifested in a broad spectrum. Classic examples of organ-specific autoimmune disease include Addison's disease, insulin-dependent type-1 Diabetes mellitus, Grave's disease (MGB), and Hashimoto thyroiditis (HT). The initial report of this autoimmune thyroid disease (AITD) dates back to Hakira Hashimoto (1912). In HT, as an organ-specific autoimmune disease, massive infiltration of lymphoid cells and parenchyma destruction are a consistent feature. The infiltration appears to be immune-mediated, primarily lymphocytic (T helper, T suppressor cells), NK cells and B cells. The pathological characteristics of AITD include development of the goitre (atrophic form is not so frequent), impaired thyroid gland function (from hyperthyroidism to subclinical and manifested hypothyroidism) and the formation of antithyroidal antibodies against thyroglobulin (AbTg) and the microsomal antigen (Ab TPO). There is a very good correlation between the antibodies against TPO and the histological findings. Morbus Graves Basedow is characterized by autoimmune hyperthyroidism with goitre, and infiltrative orbitopathy. Autoantibodies against the TSH-receptor molecule on the plasma membrane of the thyroid gland follicles cause a nonphysiological activation and an increase of the cellular function. Besides this hyperthyroidal condition, an autoimmune attack against the retrobulbar tissue leading to endocrine orbitopathy, can be noted in about 40% of patients suffering from MGB.

[Diagnosis of autoimmune thyroid disease].

Autoimmune thyroid disease (AITD) is the most common organ specific autoimmune disorder usually resulting in dysfunction (hyperfunction, hypofunction or both) of the thyroid gland. The syndromes comprising autoimmune thyroid disease are many intimately related illnesses: Graves' disease with goitre, hyperthyroidism and, in many patients, associated ophthalmopathy, Hashimoto's thyroiditis with goitre and euthyroidism or hypothyroidism but also thyroid dysfunction occurring independently of pregnancy and in 5-6% of postpartum women and thyroiditides induced by different drugs and other environmental influences. The immunological mechanisms involved in these diseases are closely related, while the phenotypes probably differ because of the specific type of immunological response that occurs. The syndromes are connected together by their similar thyroid pathology, similar immune mechanisms, co-occurrence in family groups, and transition from one clinical picture to another within the same individual over time. In some patients, other organ specific and nonorgan specific autoimmune syndromes are associated with autoimmune thyroid disease, including pernicious anemia, vitiligo, myasthenia gravis, primary adrenal autoimmune disease, celiac disease, rheumatoid arthritis or lupus. Thyroid peroxydase, TPO, the primary enzyme involved in thyroid hormonogenesis, was initially identified in 1959 as the 'thyroid microsomal antigenn. It is uncertain whether TPO autoantibodies or TPO-specific T cells are the primary cause of thyroid inflammation, which can lead, in some individuals, to thyroid failure and hypothyroidism. TPOAbs are the hallmark of AITB and are present in almost all patients with Hashimoto's thyroiditis, in two-thirds of patients with postpartum thyroiditis and also in 75% of patients with Graves' hyperthyroidism. The antibodies are mainly produced by lymphocytic infiltrate in the thyroid gland and only to a small extent by regional lymph nodes or the bone marrow. Unlike antibodies against thyroglobulin (Tg), TPO antibodies are capable of inducing antibody-dependent cell-mediated cytotoxicity. Antibodies to TSH-R mimic the function of TSH, and cause disease by binding to the TSH-R and stimulating (or inhibiting) thyroid cells. The TSHR, a member of the G protein-coupled receptor family with seven membrane-spanning segments. Patients with autoimmune thyroid disease may have both stimulating and blocking antibodies in their sera, the clinical picture being the result of the relative potency of each species; blocking antibodies seem more common in Graves' patients with ophthalmopathy compared to those without this complication. The major T cell epitopes are heterogeneous and T cell reactivity against certain TSH-R epitopes has been present in high proportion in normal subjects. More diversified response to TSH-R, with heterogeneity of epitope recognition by TSAb, is predictive of likely remission after antithyroid drug treatment for Graves' disease.

[Disorder of adrenal gland function in chronic fatigue syndrome]. / Poremecaj funkcije nadbubrega u sindromu hronicnog zamora.

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et al found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 microgram) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analysed in three subject groups: control (C), secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the i.v. injection of 1 microgram ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the i.v. cannula at 0, 15, 30, and 60 min. Data are presented as mean +/- standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However, there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 microgram ACTH in CFS and control subjects. They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve. There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et al found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently, reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.

[Subclinical thyroid disease--should we treat, should we screen for it?]. / Subklinicka tireoidna bolest--da li je leciti, da li tragati za njom?

Subclinical thyroid disease is defined by an abnormally high (subclinical hypothyroidism) or low (subclinical hyperthyroidism) serum thyrotropin (TSH) with peripheral thyroid hormone concentrations within the laboratory reference ranges. Such abnormalities in thyroid function tests are very common in the population and have been extensively dealt with in textbooks and reviews. Subclinical hypothyroidism is common especially in elderly women. There is no clear evidence to date that subclinical hypothyroidism causes clinical hearth disease. However, mild thyroid gland failure, evidenced solely by elevation of the serum TSH concentration, may be associated with increased morbidity, particularly for cardiovascular disease and subtly decreased myocardial contractility. In subclinical hypothyroidism both cardiac structures and function remain normal at rest, but impaired ventricular function as well as cardiovascular and respiratory adaptation to effort may became unmasked during exercise. These changes are reversible when euthyroidism is restored. Subclinical hypothyroidism does result in small increase in low density lipoprotein cholesterol and a decrease in high density lipoprotein, changes that enhance the risk for development of atherossclerosis and coronary artery disease. Because undetected subclinical hypothyroidism during pregnancy may adversely affect the neuropsychological development and survival of the fetus and be associated with hypertension and toxemia, screening pregnant women has been advocated. In addition, data suggesting that subclinical hypothyroidism is associated with ovulatory dysfunction and infertility may make screening worthwhile in this population as well. The combination of an undetectable serum thyrotropin concentration, as measured by an assay with a threshold of detection that is 0.1 mU per liter or less, and normal serum triiodothyronine and thyroxine concentrations (usually at the upper end of the normal range) is known as subclinical hyperthyroidism. This condition reflects the facts that before clinical features of thyrotoxicosis are apparent, the thyrotrophs usually respond to minor increments in thyroid hormone concentrations, which remain within the normal range, by switching off the production and secretion of thyrotropin. In the absence of clinical signs of thyroid disease, and even after additional investigations such as isotope uptake and imaging and measurement of the thyrotropin receptor antibody concentration, it may be difficult to decide whether the pattern seen on thyroid function tests is a consequence of nonthyroidal illness and concomitant medication, underlyling thyroid autonomous function or the initial phase of thyroiditis. Routine screening for thyroid disease with thyroid function tests is not recommended for asymptomatic children or adults. This recommendation does not mean that clinicians should not monitor thyroid function in patients with a previous history of thyroid disease. There is insufficient evidence to recommend for or against screening for thyroid disease with thyroid function tests in high-risk patients, including elderly persons, postpartum women, and persons with Down syndrome, but recommendations may be made on other grounds, such as the higher prevalence of disease and the increased likelihood that symptoms of thyroid disease will be overlooked in these patients. If screening is performed, the preferred test is measurement of thyroid-stimulating hormone (TSH) using a sensitive immunometric or similar assay, because of its superior sensitivity and specificity.

[Pancreatic carcinoid]. / Karcinoid pankreasa.

Carcinoid tumours arise from argentaffine cells or from a primitive stem cells which may differentiate into anyone of a variety of adult endocrine-secreting cells. Carcinoid tumour of the pancreas is a very rare tumour with less than 50 cases reported in world literature. In literature it is denoted "pancreatic serotoninoma" or "serotonin-producing pancreatic tumour". Due to its rarity the tumour is an unusual cause of carcinoid syndrome. As the carcinoid tumour of the pancreas does not always causes carcinoid syndrome its absence does not necessarily exclude the existence of the tumour. The tumour is frequently malignant. Over 50% of patients have metastases at the time of surgery. This is the reason why radical surgery is not possible in a number of patients. Excisional surgery offers the best chance for recovery or long term survival. We report on a 57-year-old woman with carcinoid syndrome caused by malignant carcinoid tumour of the head of the pancreas without liver or other distant metastases; it was successfully excised with pylorus preserving cephalic duodenopancreatectomy (after Longmire-Traverso) and radical lymphadenectomy. The diagnosis was established on the basis of histologic and immunohistochemical findings. The patient is symptom free for more than eight months.