Pro-A-type and N-terminal pro-B-type natriuretic peptides in different thyroid function states.

QUESTIONS UNDER STUDY: Natriuretic peptides are produced predominantly in the heart and secreted in response to volume expansion and pressure overload. A wide spectrum of cardiac changes is observed in thyroid dysfunctions. This study investigates mid regional pro A-type (proANP) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels in different thyroid states and evaluates the effect of L-thyroxine treatment on natriuretic peptides in patients with subclinical hypothyroidism. METHODS: Case-control and double-blind, placebo-controlled trial. Sera from 161 female patients (35 with overt, 63 with subclinical hypothyroidism; 10 with overt, 14 with subclinical hyperthyroidism; 40 euthyroid controls) were analysed. ProANP and NT-proBNP were measured at baseline and 48 weeks after L-thyroxine treatment in subclinical hypothyroidism. RESULTS: Circulating proANP and NT-proBNP levels were higher in hyperthyroid patients than in hypothyroid and euthyroid patients (p <0.001). Plasma proANP levels tended to be lower in overt hypothyroidism than in subclinical hypothyroidism. ProANP and NT-proBNP levels correlated weakly to thyroid stimulating hormone (TSH) (r = -0.3 and -0.2, respectively). The natriuretic peptide levels of subclinical and overt hypothyroid subjects showed no difference with those of euthyroid subjects. L-thyroxine treatment had no effect on natriuretic peptide levels in subclinical hypothyroidism. CONCLUSION: Natriuretic peptide levels are altered in different thyroid states with a more pronounced effect in hyperthyroidism than in hypothyroidism. Hyperthyroidism should be considered in patients presenting with unclear symptoms and mildly elevated natriuretic peptide levels, as overt hyperthyroidism results in increased serum A- and B-type natriurectic peptide levels, typically seen in mild heart failure.

Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function.

The metyrapone test is used to test the hypothalamic-pituitary-adrenocortical axis. The present study aims to assess the diagnostic accuracy of combined stimulation of ACTH and compound-S (CMP-S). In addition, we analyzed the safety and practicability of this test as an outpatient procedure. A total of 327 metyrapone tests were analyzed retrospectively in 185 patients (mean age, 50.3 +/- 15.2 yr). One hundred thirteen patients had one test, and 72 patients had between 2 and 6 tests over 1-3 yr. Most patients suffered from pituitary adenomas (60 macroadenomas, 63 microadenomas) or other pituitary lesions (n = 29). Metyrapone (2 g) was given at 2400 h as an outpatient procedure. Blood samples for analysis of ACTH, CMP-S, and cortisol were taken at 0730 h. Stimulation of adrenal CMP-S and cortisol by pituitary ACTH demonstrated a dose-response curve with the shape of half a geometric parabola. CMP-S reached a plateau when ACTH rose above 175 ng/liter [r = 0.661, P < 0.0001 for ACTH <175 ng/liter; r = 0.083, P = not significant (NS) for ACTH >175 ng/liter], cortisol flattened at ACTH levels above 230 ng/liter (r = 0.633; P < 0.0001 for ACTH < 230 ng/liter; P = NS for ACTH >230 ng/liter). Alternatively, the sum of CMP-S plus cortisol also flattened when ACTH rose above 230 ng/liter (r = 0.696; P < 0.0001 for ACTH <230; P = NS for ACTH > 230 ng/liter). Receiver operating curve analysis defining a cut-off for ACTH at 150 ng/liter demonstrated a sensitivity of 47% and 67% at a cut-off level for CMP-S at 200 or 260 nmol/liter, respectively. The respective specificity was 82% and 68% for CMP-S. This compared with a sensitivity of 71% and specificity of 69% if the sum of CMP-S plus cortisol of 450 nmol/liter were used as cut-off. The response curve between CMP-S and ACTH implies a maximally stimulated adrenal cortex at circulating ACTH levels above 175 ng/liter. Single measurement of CMP-S using the cut-off at 200 nmol/liter, as suggested in the literature, yields a poor sensitivity of only 47% compared with ACTH. Despite the relatively high cross-reactivity of CMP-S in the cortisol assay, the sum of CMP-S and cortisol levels with a cut-off value of 450 nmol/liter yields a better diagnostic accuracy compared with CMP-S alone.

Basal TSH levels compared with TRH-stimulated TSH levels to diagnose different degrees of TSH suppression: diagnostic and therapeutic impact of assay performance.

BACKGROUND: The estimated prevalence of endogenous subclinical hyperthyroidism varies from 4% to 6% and a basal thyroid stimulating hormone (TSH) level < 0.5 mU L-1 may be associated with increased mortality in subjects over 60 years of age who are not on thyroid medication. Exogenous TSH suppression is a mainstay in the treatment of thyroid cancer. Because of recent concerns about potential adverse effects, especially of endogenous TSH suppression on bone, the cardiovascular system and cognitive functions, subclinical hyperthyroidism obtained new clinical importance. We therefore re-evaluated the diagnostic value of basal and thyrotrop in TRH-stimulated serum TSH measurements using TSH assays with different sensitivities. MATERIALS AND METHODS: A total of 805 oral and nasal TRH stimulation tests were performed on 409 ambulatory subjects with low basal serum TSH concentrations of less than 0.1 mIU L-1. Basal serum TSH was measured either using a second generation assay (functional sensitivity > 0.03 mIU L-1) or two third generation assays (functional sensitivity 0.01 mIU L-1 and 0.007 mU L-1, respectively). Serum TSH concentration was determined before and 3 h after oral administration of 40 mg of TRH and before and 30 min after nasal administration of 2 mg of TRH. RESULTS: In the oral testing group, the basal TSH levels measured by the different TSH assays were 0.06 +/- 0.03, 0.04 +/- 0.02 and 0.03 +/- 0.02, respectively, whereas the peak TSH levels were 0.4 +/- 0.6, 0.4 +/- 0.6 and 0.3 +/- 0.5 in the patients with subclinical hyperthyroidism. In overt hyperthyroidism, the basal TSH levels were 0.06 +/- 0.02, 0.03 +/- 0.02 and 0.03 +/- 0.02, whereas the peak TSH levels were 0.19 +/- 0.3, 0.16 +/- 0.3 and 0.15 +/- 0.2, respectively. Basal TSH values could discriminate between different degrees of TSH suppression if measured with a third generation assay (P < 0.001), but not with a second generation assay. There was only a weak correlation between basal TSH and peak TSH when measured by a second generation assay (n = 126; r = 0.3; P < 0.001) in contrast to the strong correlation found using the third generation assays (n = 128; r = 0.7; P < 0.001 and n = 69; r = 0.8; P < 0.001, respectively). CONCLUSIONS: In view of the recent concerns about potential adverse effects in TSH suppression and based on our data, it is mandatory to select a TSH assay with a functional sensitivity of < or = 0.01 mIU L-1 for optimal titration of L-T4 suppressive therapy, especially in patients with thyroid cancer. If, however, only a second generation TSH assay is available, additional TRH testing allows a more careful titration of suppressive thyroxine therapy.

TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study).

This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L-thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced [-0.24 mmol/liter, 3.8% (P = 0.015) and -0.33 mmol/liter, 8.2% (P = 0.004), respectively]. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol.

Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease.

The influence of thyroid failure on haemostasis is controversial, both hypocoagulable and hypercoagulable states have been reported. Since both subclinical and overt hypothyroidism have been associated with atherosclerosis, a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. We investigated various haemostatic variables in 42 women with subclinical hypothyroidism and compared them to 66 euthyroid controls. Prothrombin time, activated partial thromboplastin time, fibrinogen, factor VII activity (FVII:C), factor VII antigen (FVII:Ag), factor VIII activity, von Willebrand factor (vWF), antithrombin III, heparin cofactor II, protein C, protein S, plasminogen, antiplasmin, plasminogen activator inhibitor and tissue plasminogen activator, as well as common lipid variables, were measured. Factor VII:C (P < 0.02) and the ratio FVII:C/FVII:Ag (P < 0.01) were significantly increased in subclinical hypothyroid patients compared to the control group. Both parameters remained higher in hypothyroid patients after exclusion of 18 women on oestrogen replacement therapy. No differences were found between the groups with respect to vWF or the other haemostatic and lipid variables tested. Patients with subclinical hypothyroidism had significantly higher levels of FVII:C. The greater increase in FVII:C compared to that of FVII:Ag, as shown by the increase in their ratio, might reflect the presence of activated FVIIa. This might mean a hypercoagulable state, which could contribute to the increased prevalence of coronary heart disease reported in such patients. A hypercoagulable state might be another argument in favour of thyroxine replacement treatment in subclinical hypothyroidism, especially in patients with additional risk factors for vascular disease.

[Amiodarone-induced thyrotoxicosis]. / Amiodaron-induzierte Hyperthyreose.

Amiodarone is the most important drug in the treatment of ventricular arrhythmias and is widely used for atrial fibrillation. Thyrotoxicosis, a classical side effect, was thought to be iodine induced, but recent evidence suggests that other mechanisms play an important role (toxic effect on thyreocytes, immunological effects). Thyrotoxicosis due to amiodarone is difficult to treat and is further complicated by the pro-arrhythmic potential of thyrotoxicosis and the fading antiarrhythmic effect after amiodarone withdrawal. The mechanism, diagnosis and therapy of amiodarone-induced thyrotoxicosis are discussed in the light of the available literature.

[Malignant pheochromocytoma in the 17th week of gestation]. / Ein malignes Phäochromocytom in der 17. Schwangerschaftswoche.

INTRODUCTION: Pheochromocytoma during pregnancy is rare and represents a high risk for mother and fetus. Due to the variable clinical presentation it may be mistaken for preeclampsia. CASE: A 34-year-old primipara with hypertension up to 240/120 mmHg. After diagnosis of a pheochromocytoma its resection together with lymph node metastasis in the 17th week of gestation was performed. CONCLUSION: The definitive diagnosis is confirmed by elevation of serum catecholamines and their metabolites in a 24-h urine collection. Localization during pregnancy can be made by ultrasound and MRI. The definitive treatment is surgical removal after administration of adrenergic blockers. If discovered later in pregnancy, delivery by elective caesarean section followed by tumor resection is recommended. Since about 10 % of pheochromocytomas are malignant, postpartum screening is required to detect and treat extraadrenal or metastatic tumors by MIBG scintigraphy, chemotherapy or surgical procedures.

[Is there a need for treatment in subclinical hypo- and hyperthyroidism?]. / Sind subklinische Hypo- und Hyperthyreosen behandlungsbedürftig?

Subclinical thyroid dysfunction is characterized by normal levels of thyroid hormones but abnormal values of thyrotropin (TSH) in an asymptomatic individual. Subclinical hypothyroidism is a common disorder with a prevalence of about 7 to 8% in women (most frequently in females over 50 years), and about 3% in men. It is characterized by elevated serum TSH in the presence of normal concentrations of serum thyroxine. Patients with TSH levels about 12 mU/L (and with positive antithyroidal antibodies) have the highest risk for developing overt hypothyroidism. Therefore, these patients will require L-thyroxine treatment. In patients with TSH < 12 mU/L, the indication for therapy depends on the etiology, on risk factors and concomitant diseases (e.g. strumectomy, coronary heart disease, depression, infertility). Subclinical hyperthyroidism (TSH suppression syndrome) is characterized by normal thyroid hormone concentrations but diminished serum TSH. Most frequently, this disorder is caused by exogenous L-thyroxine treatment. The endogenous form of subclinical hyperthyroidism mainly caused by nodular goiter has a prevalence of up to 20% in patients with large goiters. In patients with subclinical hyperthyroidism, there is an increased risk for development of atrial fibrillation and for a decrease in bone mass in postmenopausal women. In the majority of patients measurable TSH levels can be detected before or after stimulation with TRH. This formally excludes overt hyperthyroidism in such patients. Frequently, there is no need for treatment but follow-up is important. However, in patients with subclinical hyperthyroidism associated with atrial fibrillation a therapy with antithyroid drugs, beta-blockers or radioiodine must be considered.

Reversible cerebral ischemia in patients with pheochromocytoma.

Cerebral ischemia and symptoms of stroke can occur as a rare manifestation in patients with pheochromocytoma. We describe a 45-year-old woman who was admitted because of a right-sided hemiparesis due to an ischemic lesion in the left hypothalamus. The clinical diagnosis of a pheochromocytoma was proven by highly elevated urinary catecholamines and confirmed histologically after operation. The successful removal of the tumor led to the almost complete recovery of the neurological deficiencies. It is of vital importance to know this atypical presentation of pheochromocytoma. The diagnosis of pheochromocytoma should be suspected in patients with focal cerebral symptoms, particularly in the presence of intermittent hypertension or other paroxysmal symptoms suggestive of pheochromocytoma.

[Functional dynamics of impending overt hypothyroidism: spontaneous evolution in patients in the years before the beginning of treatment]. / Funktionsdynamik in der Frühphase der manifesten Hypothyreose: Spontanverlauf bei Patientinnen in den Jahren vor Therapiebeginn.

The syndrome of subclinical hypothyroidism, with its clinical and metabolic consequences, is frequent. Only a minority of these patients will eventually become overtly hypothyroid. It was the aim of the present study to analyse the spontaneous evolution over 10 years of 27 patients with subclinical hypothyroidism who became overtly hypothyroid (group A). For comparison, 27 patients remaining subclinically hypothyroid and matched for their TSH concentrations were characterised (group B). In group A, continuous increase of TSH concentrations was observed over the whole observation period (p = 0.002; ANOVA). The concentrations of fT4 remained initially stable, and only fell at a late stage in the three years before overt hypothyroidism (p = 0.0001; ANOVA). The concentrations of total T3 remained normal throughout the observation period. Thyroid reserve was already impaired at the beginning and during the whole study period. In contrast, these thyroid parameters of patients of group B remained unchanged over 10 years, and thyroid reserve remained normal. The pathogenesis of overt hypothyroidism is a graded process. Increasing concentrations of TSH, a decrease of fT4 and impaired thyroid reserve are predictors of overt thyroid failure.

[Ultrasensitive TSH screening for detection of thyroid gland dysfunctions in women of a medical ambulatory care patient group]. / Ultrasensitives TSH-Screening zur Erfassung von Schilddrüsendysfunktionen bei Frauen eines ambulanten medizinischen Krankenguts.

This aim of the study was to identify the prevalence of unsuspected thyroid dysfunction in a female population attending a medical primary care unit (case-finding study). A TSH assay of the third generation was used as a screening test. The overall prevalence of unsuspected thyroid dysfunction in 1061 female patients was 2.5% (0.5% overt hyperthyroidism, 0.3% overt hypothyroidism, 0.5% subclinical hyperthyroidism, and 1.2% subclinical hypothyroidism). The prevalence of thyroid disease is clearly age dependent with 4.3% over the age of 40 and 5.9% for 50-60 year-olds. The ratio for females below 40 and over 40 was 10.75 (Odds ratio, p < 0.0001). We conclude from our study and from the literature that TSH screening as a case-finding strategy is indicated, and also seems cost-effective, in women over 40 years of age.

[Long-term study of subclinical hypothyroidism: spontaneous course and predictors of manifest hypothyroidism]. / Langzeitstudie bei subklinischer Hypothyreose: Spontanverlauf und Prädiktoren der manifesten Hypothyreose.

The syndrome of subclinical hypothyroidism is frequent and predominantly affects females over 40. Only limited data on its natural course is available. It was the aim of our prospective trial to analyze the spontaneous evolution of this syndrome, to identify risk factors of the development of overt hypothyroidism and to develop guidelines for the management of such patients. 154 female patients were followed over a mean observation period of 10 years. After 10 years, 34% had developed overt hypothyroidism, 57% remained in the subclinical stage, and in 9% thyroid function had normalized. The initial grading of TSH-concentration (< 6 mU/l, 6-12 mU/l, > 12 mU/l) was highly predictive for thyroid failure: 7.3%, 25% and 78%, respectively, overt hypothyroidism occurred. Further risk factors for thyroid failure included an impaired thyroid reserve (T3-stimulation after TRH) and elevated titers of microsomal antibodies. We therefore recommend to controlling patients with a TSH-concentration < 6 mU/l, start thyroxine hormone replacement therapy in patients with a TSH-concentration > 12 mU/l and, depending on the additional risk factors, either controlling or treating patients with a TSH-concentration of 6-12 mU/l.

[Hyperthyroidism and thyroid carcinoma--coincidence or association?]. / Hyperthyreose und Schilddrüsenkarzinom--Koinzidenz oder Assoziation?

In a series of 617 patients undergoing thyroidectomy, 86 cases (13.9%) were identified as having hyperthyroidism. Forty-nine out of these 86 patients suffered from Graves disease. Histopathologic evaluation revealed a low grade papillary thyroid carcinoma in two out of the 86 specimens from the hyperthyroid patients. Therefore, the incidence of malignancy among all our patients with hyperthyroidism is 2.3% and among those with Graves disease is 4.1%. Patients with hyperthyroidism and concurrent nodular or diffuse goiter are at possible risk for thyroid carcinoma. The indication for surgical resection is given in these cases where the success of thyroistatic treatment is low and where patients are at higher risk for thyroid malignancy. In a short review of the literature, we discuss the coincidence of the two pathologic entities and their possible association.

Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls.

The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol. Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 +/- 2.7 vs. 4.4 +/- 2.2 vs. 3.4 +/- 2.0; P < 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 +/- 1.6 vs. 2.1 +/- 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P < 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P < 0.0004), and that with T3 was r = -0.56 (P < 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005). Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.

[Detection of RET-proto-oncogene mutations in the diagnosis of Type 2 endocrine neoplasia (MEN 2)]. / Nachweis von RET-Proto-Onkogen-Mutationen zur Diagnostik der multiplen endokrinen Neoplasie Typ 2 (MEN 2).

We have analyzed 95 blood- and 25 paraffin-derived DNA samples of 120 individuals from Switzerland (MEN 2 family members and patients with medullary thyroid carcinoma or pheochromocytoma) for the presence of RET protooncogene mutations in exons 10, 11, 13, 14 and 16, where recently germline point mutations have been identified in more than 95% of patients with MEN 2A, familial medullary thyroid carcinoma (FMTC) and MEN 2B. Molecular DNA screening of samples was performed by non-radioactive single strand conformation polymorphism (SSCP) and heteroduplex gel electrophoresis method followed by mutation analysis of PCR products by direct cycle sequencing using an automated DNA sequencer. We identified 12 MEN 2A/FMSC and 6 MEN 2B families with 29 gene carriers. Ten different types of mutations were identified in the MEN 2A/FMTC families (620 Cys-->Arg, 618 Cys-->Ser, Gly, 611 Cys-->Tyr; 634 Cys-->Arg, Tyr, Trp, Phe, Ser, Gly) and all 6 MEN 2B families had a 918 Met-->Thr point mutation. Our results indicate that PCR-based DNA testing for RET point mutations is a rapid, accurate and reproducible method of identifying MEN 2 gene carriers using blood or tissue DNA. Early detection of gene carriers allows preventive thyroidectomy without neck dissection or parathyroid transplantation, and non-gene carriers can be released from biochemical testing. Furthermore, it is shown that the distribution and localization of RET mutations in MEN 2 families from Switzerland concur with combined results of larger series and that a "founder effect" of MEN 2 can be excluded for this country.