Follicular nodules (THY3) of the thyroid: we recommend surgery.

OBJECTIVE: To determine the need of total thyrodectomy for patients with follicular nodules of thyroid. SUBJECTS AND METHODS: From January 2005 through June 2008, 2249 consecutive patients (438 males, 1811 females; mean age 54 yr, range 9-87) with thyroid nodules were submitted to 2518 ultrasound-guided fine-needle aspiration (USgFNA) for cytological examination. USgFNA were performed by experienced surgeon (RP) and endocrinologist (RGG) under ultra- sonographyc guidance, using a 10-MHz linear transducer. Liquid-based cytology was used. RESULTS: All cytological samples were classified in 5 diagnostic classes (THY1, THY2, THY3, THY4, THY5) in agreement with the British Thyroid Association (BTA); 1.4% specimen were classified as THY5, 2.1% as THY4, 7.6% as THY3, 79.5% as THY2 and 9.4% as THY1. In 97% of THY5 patients, malignancy was found. Among THY4 patients, 95.5% were positive for thyroid tumor. Among THY3 patients, malignancy was found in 29.1%. THY3 patients with thyroid tumors were younger than those with benign lesions (46 ± 14.1 yr vs 50 ± 13.8 yr; p<0.05, t test). No statistical difference was found neither in malignancy frequency among men and women nor in mean size of nodules (24 ± 11.8 mm malignant vs 23 ± 9.4 mm benign). CONCLUSIONS: this study provides evidence that USgFNA offers a very sensitive and accurate method in reducing THY1 samples and in detecting malignancy (>95% both in THY5 and THY4, and >29% in THY3 lesions). Our proposal is to submit to total thyroidectomy all patients with THY5 and THY4 lesions and THY3 thyroid nodule >1 cm.

Gestational diabetes insipidus: a morphological study of the placenta.

Gestational diabetes insipidus (GDI) refers to the state of excessive water intake and hypotonic polyuria. Those cases manifesting in pregnancy and referred to as GDI may persist thereafter or may be a transient latent form that resolves after delivery. Microscopic examination of affected subjects has not been previously reported. In the literature, there are various case reports and case series on diabetes insipidus in pregnancy. In this study, we present a case that had transient diabetes insipidus during pregnancy in which the placenta was examined.

Distributional map of the terminal and sub-terminal sugar residues of the glycoconjugates in the prepubertal and postpubertal testis of a subject affected by complete androgen insensitivity syndrome (Morris's syndrome): lectin histochemical study.

In the present research we have investigated the distribution of the sugar residues of the glycoconjugates in the prepubertal and postpubertal testes of a subject with Morris's syndrome (CAIS, Complete Androgen Insensitivity Syndrome). For this purpose a battery of six horseradish peroxidase-conjugated lectins was used (SBA, PNA, WGA, ConA, LTA and UEAI). We have obtained a complete distributional map of the terminal and sub-terminal oligosaccharides in the tunica albuginea, interstitial tissue, lamina propria of the seminiferous tubules, Leydig cells, Sertoli cells, spermatogonia, mastocytes and endothelial cells. Furthermore the present study has shown that a large amount of sugar residues were detectable in the prepubertal and postpubertal testes but that some differences exist with particular regard to the Sertoli cells. The Sertoli cells and the Leydig cells of the retained prepubertal testis of the patient affected by Morris's syndrome were characterized by the presence of alpha-L-fucose, which was absent in the retained prepubertal testis of the normal subjects. Comparing the results on the postpubertal testis with those obtained on the same aged testis of healthy subjects we have demonstrated that alpha-L-fucose in the Sertoli and Leydig cells and D-galactose-N-acetyl-D-galactosamine in the Leydig cells are a unique feature of the subject affected by Morris's syndrome. D-galactose (ss1,3)-N-acetyl-D-galactosamine and sialic acid, which are present in the Leydig cells of the normal testis were never observed in the same cells of the postpubertal testis of the CAIS patient.

Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias.

The clinical features and the laboratory aspects of the amiodarone-induced hypothyroidism (AIH) in the elderly as well as the effects of amiodarone treatment in aged AIH people have not yet been well clarified. In the present paper, we evaluated 18 subjects of both sexes (7 females, 11 males), aged 65-83 years, affected by AIH, recruited in Central Tuscany, Italy. The patients were divided in two subsets on the basis of thyroid stimulating hormone (TSH) values: mild (TSH < 20 mU/l; Group A, n=11) and severe (TSH > 20 mU/l; Group B, n=7) hypothyroid patients. On the basis of clinical features, hypothyroidism was diagnosed only in two patients (out of Group B). Concerning the hormonal pattern, we found that free tetraiodothyronine (fT4) levels were significantly lower than the normal range only in Group B subjects; TSH and thyroglobulin were higher than normal in both groups; free triiodothyronine (fT3) were always in the normal range. Thyroid autoantibodies were found positive only in one patient out of Group A and in two patients out of Group B. In 5/18 patients T4 substitutive therapy was rapidly assigned, because of severe degree of hypothyroidism. In the remaining 13/18 patients, we evaluated the clinical behavior of AIH. After additional cardiac evaluation, amiodarone was withdrawn in 5/13 patients: during follow-up period (4-10 months) four patients became quickly euthyroid while one worsened. In 8/13 patients, amiodarone treatment had to be carried on; during follow-up (2-48 months), four patients remained mildly hypothyroid, while other four patients became severely hypothyroid. In conclusion, in amiodarone treated elderly people, diagnosis of hypothyroidism is reliable only on the basis of high values of TSH; clinical features and fT3 serum levels never enable diagnosis.

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

[Subclinical hyperthyroidism and hypothyroidism]. / Gli ipertiroidismi e gli ipotiroidismi subclinici.

Currently, technical methods to obtain precocious and reliable diagnosis of thyroid disorders are available for physicians. Therefore today, patients affected by mild hypo- or hyperthyroidism are more often diagnosed when they are still asymptomatic; these mild forms of thyroid disorder are known as subclinical hypo- and hyperthyroidism. In comparison with '80ties, over the last few years we have observed that patients come to endocrinological examination for subclinical forms of thyroid disorders (particularly for hypothyroidism) more frequently than for severe thyroid diseases. However, before to start a therapy, it is necessary for these patients to determine the causes of subclinical hypo- and hyperthyroidism. The main goals of therapy are to reduce the prevalence of cardiac arrhythmia and osteoporosis of patients with subclinical hyperthyroidism, and to slow down the course of arteriosclerotic disease (linked to hyperlipidemia and/or to hyperhomocysteinemia) of patients with subclinical hypothyroidism.

Two-step development of a pituitary adenoma: from hyperprolactinemic syndrome to Cushing's disease.

In this report we describe the case of a young female patient with amenorrhea-galactorrhea syndrome apparently due to pituitary PRL-secreting adenoma who, after three years of dopaminergic therapy without any shrinkage of the tumor, developed true Cushing's disease. Progression from hyperprolactinemia to hypersecretion of ACTH has been rarely described and it may be due to different possibilities. However, histopathological and immunohistochemical studies of the adenoma showed a pattern of PRL negative and ACTH positive cells, excluding mixed pituitary tumor. In order to explain the progression from hyperprolactinemia with amenorrhea-galactorrhea to an ACTH hypersecretion syndrome, it must be hypothesized either pituitary stalk compression or the influence of paracrine regulation factor(s) (such as Galanine) due to an "initially silent" corticotropinoma. This case confirms that the presence of hyperprolactinemia in a patient with pituitary tumor and amenorrhea-galactorrhea syndrome is insufficient to confidently conclude for prolactinoma. Furthermore, it underlines the importance both of clinically monitoring the patient with prolactin pituitary adenoma if dopaminergic therapy does not reduce tumor volume, and of accurately and repeatedly measuring the other pituitary hormonal secretions.

Signal-averaged P-wave duration and risk of paroxysmal atrial fibrillation in hyperthyroidism.

The onset of atrial fibrillation (AF) in hyperthyroid patients constitutes an unfavorable clinical event associated with high risk of cardiovascular complications, occurring in approximately one fifth of patients. Therefore, it is advantageous to define noninvasive markers that may identify patients at risk. The high-resolution, signal-averaged electrocardiogram was used to evaluate the relation between P-wave duration and occurrence of paroxysmal AF in a group of 50 patients with hyperthyroidism, of whom 24 had a history of paroxysmal AF and 26 did not. Filtered signal-averaged P-wave duration was measured over an average of 300 beats/patient while in sinus rhythm, both at the time of first diagnosis of hyperthyroidism and after restoration of euthyroidism by medical treatment. The 24 patients with paroxysmal AF had significantly greater P-wave duration than the 26 patients without it (135 +/- 7 vs 124 +/- 9 ms; p = 0.001). A P-wave duration cut-off value of 130 ms held specificity, sensitivity, and positive predictive accuracy values of 79%, 85%, and 83%, respectively. Of several variables, multivariate analysis showed P-wave duration to be the only independent variable significantly associated with the occurrence of paroxysmal AF. Thus, the high-resolution signal-averaged electrocardiogram may be a useful noninvasive clinical tool for the identification of electrical instability associated with paroxysmal AF in hyperthyroid patients.

Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group.

OBJECTIVES: Pheochromocytoma (pheo) is the second component of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. Clinical expression is sometimes poor, and chronology between medullary thyroid carcinoma (MTC) and pheo is not well evaluated. Therefore, a retrospective study was done in eight European countries in order to precise the main characteristics of pheo in MEN 2. SUBJECTS: Data from 300 MEN 2 patients with pheo (274 MEN 2 A and 26 MEN 2 B) were obtained from cases registered by the EuroMen study group, and collected by a medical standardized questionnaire. These cases occurred between 1969 and 1992. RESULTS: Mean age at diagnosis of pheo was 39.5 years (range 14-68 years) in MEN 2A and 32.4 years (range 15-41 years) in MEN 2B patients. Pheo occurred first in 25.1% of the cases (2-15 years before diagnosis of MTC) and after MTC in 40.2% (2-11 years). In other cases (34.7%), MTC and pheo were diagnosed at the same time. Involvement was bilateral in 67.8% of cases. Malignancy was only 4%. Thirty-nine deaths occurred in these 300 patients, 64.1% were linked in pheo, 23.1% to MTC and 12.8% to other causes. Surgery was unilateral in 39.7% of the cases and bilateral adrenalectomy was the first procedure in 48.4%. A bilateral adrenalectomy in two steps had to be done in 11.9% of cases. In conclusion, these results justify systematic and prolonged biochemical screening of pheo during follow-up of MTC and address some questions about the best mode of surgery.

Usefulness of early morning urine estrone-3-glucuronide assay in the monitoring ovarian secretory function in precocious puberty.

To evaluate the usefulness of the urinary estrone-3-glucuronide (EI-3-G) in the monitoring of the ovarian function in girls, we studied 11 girls with idiopathic central precocious puberty (ICPP) treated with LHRH analogs (LHRHa) for 2-5 years. Plasma LH, FSH, 17-beta-Estradiol (E2) levels, early morning urine (EMU) E1-3-G concentrations, were assessed before and 3, 6, 12 months after the onset of treatment. As expected, mean basal plasma LH, FSH and E2 concentrations, as well as mean basal EMU E1-3-G levels were significantly (p < 0.01) higher in patients studied than in normal, age matched, prepubertal controls. Three out of the 11 sexually advanced girls showed undetectable (< 15 pg/ml) basal plasma E2 values. On the contrary, in each patient studied, individual basal E1-3-G levels were higher than in normal age-matched prepubertal girls. LHRHa treatment significantly suppressed both basal and peak stimulated plasma gonadotropins, plasma E2 and EMU E1-3-G. However, while serum E2 levels were below the assay detection limit, not allowing to assess the degree of gonadal suppression, E1-3-G urinary concentrations were detectable in each subject treated, in the range of the normal prepubertal values. EMU E1-3-G determination seems to be a very sensitive and reliable approach to the monitoring of the effectiveness of LHRHa treatment in sexually advanced girls, allowing to detect very low estrogen concentrations and to achieve the desired ovarian suppression.

Precocious puberty: auxological criteria discriminating different forms.

It may be possible to recognize different forms of precocious puberty at the first evaluation. In a group of 26 sexually precocious girls we used Bayley-Pinneau predicted adult height (P.A.H.) to discriminate patients with 'poor' or 'good' height prognosis. Patients with evidence of impaired height prognosis (P.A.H. < -1 SDS) (Group 1) were immediately treated with LH-RH analogs, while patients with unimpaired height prognosis (P.A.H. > -1 SDS) (Group 2) were followed without therapy. Two yr of treatment significantly improved P.A.H. in Group 1 patients, from a mean of -1.68 +/- 0.4 to a mean of -0.57 +/- 0.6 (SDS) (p < 0.01). After the 2 yr observation period, Group 2 patients showed no significant variation of P.A.H. (from a mean of 0.45 +/- 0.8 to a mean of 0.33 +/- 0.6). The retrospective analysis of the growth pattern changes in the two Groups seems to indicate that LH-RH agonist treatment improves height potential in girls with initial poor height prognosis and that girls with initial good height prognosis maintain an unimpaired growth potential.

Control of breathing in patients with severe hypothyroidism.

PURPOSE: Hypothyroid patients have been reported to have a blunted ventilatory response to carbon dioxide stimulation. However, previous data did not clarify the localization of abnormalities responsible for that disorder. The present investigation was aimed at evaluating to what extent central (neural) and/or peripheral (muscular) factors are involved in the abnormalities of the ventilatory control system in hypothyroid patients. PATIENTS AND METHODS: We studied 13 patients with severe hypothyroidism before and after 6 to 9 months of replacement therapy; 7 age- and sex-matched normal subjects were also studied as a control. In each subject, we assessed (1) inspiratory muscle strength by measuring maximal inspiratory pressure (MIP), and (2) respiratory control system during a carbon dioxide rebreathing test by measuring minute ventilation (VE), tidal volume (VT), mean inspiratory flow (VT/TI), and electromyographic (EMG) activity of the diaphragm (Edi) and intercostal (Eint) muscles. RESULTS: Compared with the normal control group (Group C), patients exhibited similar MIP, and similar VE and EMG response slopes to carbon dioxide. However, evaluating individual VE response slopes, we were able to identify two subsets of patients: Group A (six patients) with low VE response (less than mean -SD.1.65 of Group C) and Group B (seven patients) with normal VE response. Compared with both Groups B and C, Group A exhibited significantly lower VT/TI, Edi, and Eint response slopes; the difference between Groups B and C was not significant. Six patients (two from Group A and four from Group B) exhibited low MIP values compared with that in Group C. After replacement therapy, (1) VE, VT/TI, and Edi response slopes increased significantly in Group A; and (2) MIP increased, but not significantly in patients with low MIP. CONCLUSIONS: We conclude that: (1) In patients with severe hypothyroidism, the ventilatory control system may be altered at the neural level, as indicated by a blunted chemosensitivity; (2) Impaired respiratory muscle function does not seem to play a major role in the decreased ventilatory response to carbon dioxide stimulation; (3) Replacement therapy appears to normalize the response to hypercapnic stimulation, but not respiratory muscle strength.

Oxandrolone in constitutional delay of growth: analysis of the growth patterns up to final stature.

In order to evaluate the effects of low-dosage, 6-12 months course of oxandrolone treatment in constitutional delay of growth, we compared the growth responses on treatment, the pattern of sexual development and pubertal growth events, up to final stature of 11 prepubertal boys, aged 10.6-14.1 yr, with those of 11 prepubertal, age-matched untreated controls. Treatment caused a significant increase of height velocity, from 4 to 9 cm/yr, and a significant acceleration of bone maturation, without affecting the timing of onset of puberty, the progression of sexual development or the onset of pubertal growth spurt. On the other hand, oxandrolone induced an earlier skeletal growth arrest but did not affect the expected final height. Treated boys showed an adult stature not significantly different from that of control subjects. Our data suggest that 6 months-1 year, low dosage oxandrolone treatment in constitutionally delayed growth has no significant effect on the pattern of pubertal growth, nor on the rate of sexual maturation or on final height.

Increased acylphosphatase levels in erythrocytes from hyperthyroid patients.

Acylphosphatase activity and content were measured in erythrocytes from hyperthyroid patients and healthy controls. In addition, the soluble enzymes glucose-6-phosphate dehydrogenase, hexokinase, and the membrane bound (Na+ + K+)-ATPase and Ca2+-ATPase were assayed. Our results confirmed previous studies indicating a decrease of (Na+ + K+)-ATPase and an increase of Ca2+-ATPase activity in hyperthyroid erythrocytes. While glucose-6-phosphate dehydrogenase was not significantly changed, hexokinase and acylphosphatase activities were significantly higher in the hyperthyroid group. Both activities and content of acylphosphatase returned to normal levels in erythrocytes from treated patients, when they were euthyroid. These findings suggest that an excess of thyroid hormones may stimulate acylphosphatase biosynthesis in erythroid cells and indicate a potential clinical usefulness of this enzyme in hyperthyroidism.

[Acute antiarrhythmia treatment with amiodarone and blood levels of thyroid hormones]. / Trattamento antiaritmico acuto con amiodarone e livelli ematici degli ormoni tiroidei.

Amiodarone has a good antiarrhythmic effect administered either acutely or chronically. Since the antiarrhythmic effect of chronically administered amiodarone has been thought to be dependent on a depression of thyroid function, we studied the peripheral hormonal pattern of 10 euthyroid patients with ventricular arrhythmias who had been responsive to the acute intravenous administration of the drug (10 mg/Kg). During the first 12 hours following the drug administration, reverse T3, free T3 and free T4 values and QTc duration were unchanged. Therefore the antiarrhythmic effect of amiodarone when acutely administered has no correlation with thyroid hormone serum changes.

A new case of familial partial generalized resistance to thyroid hormones: study of 3,5,3'-triiodothyronine (T3) binding to lymphocyte and skin fibroblast nuclei and in vivo conversion of thyroxine to T3.

A clinically euthyroid 30-yr-old man with high serum levels of both total (T4, 14.5 micrograms/dl; T3, 272 ng/dl) and free (FT4, 33 pg/ml; FT3, 9.7 pg/ml) thyroid hormones and inappropriately normal TSH levels, both basally and after TRH stimulation, is described. Peripheral indices of thyroid hormone action and the patient's clinical status were not modified by the prolonged administration of supraphysiological doses of both T4 (up to 900 micrograms/day) and T3 (up to 80 micrograms/day), which decreased but did not completely abolish the TSH response to TRH. However, the TSH response to TRH was normally blunted by dexamethasone administration, which also reduced serum T4 and T3 levels to normal. T3 binding to nuclei of mononuclear leukocytes and cultured skin fibroblasts was normal. The overall pattern demonstrates that the patient was affected by partial peripheral resistance to thyroid hormone action. Study of the patient's family revealed the same hormone pattern in the patient's father, suggesting an autosomal dominant mode of inheritance. An in vivo study performed after the iv injection of tracer doses of [125I]T4 and [131I]T3, demonstrated increased production rates (PR) of both T4 [PR, 113.0 micrograms/day X m2; normal subjects, 55.4 +/- 12.3 (mean +/- SD); n = 13] and T3 (PR, 41.1 micrograms/day X m2; normal subjects, 16.3 +/- 2.7). In vivo conversion of T4 to T3 was also evaluated in the patient; a nearly normal T4 to T3 conversion factor was found (0.3108 vs. 0.2576 +/- 0.0422 in normal subjects). In four hyperthyroid patients, the T4 to T3 conversion factors were similar (0.2932 +/- 0.0600), while the PRs of T4 and T3 were increased (PR of T4, 308.6 +/- 85.6; PR of T3, 110.3 +/- 35.0 micrograms/day X m2) compared to those in the normal subjects.

Plasma catecholamine response to orthostasis in longstanding hypothyroidism.

In seven normotensive women affected by long-standing hypothyroidism norepinephrine peripheral levels were found significantly higher than after replacement therapy and than normal controls. After standing norepinephrine peripheral concentrations increased further; such an increase, although percentually lower than after therapy was sufficient to assure an adequate clinical response to orthostasis.