Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients.

PURPOSE: This prospective study evaluated the recurrence rate in 715 patients with differentiated thyroid cancer who had no evidence of persistent disease after total thyroidectomy and lymph node dissection in 94% of them followed up by radioiodine ablation (30-100 mCi) and assessed the predictive value of the initial thyroglobulin (Tg) levels for detecting recurrence, both during levothyroxine (LT4) treatment and after TSH stimulation. PATIENTS AND METHODS: Patients had Tg determinations performed at 3 months on LT4 treatment (Tg1) and at 9-12 months after stimulation by either thyroid hormone withdrawal or recombinant human TSH (Tg2); the Access kit was used (functional sensitivity of 0.11 ng/ml); they had undetectable anti-Tg antibodies. Patients were followed up annually. Predictive values were calculated by comparing Tg levels (Tg1 and Tg2) and the outcome in terms of recurrence. RESULTS: During the median follow-up of 6.2 yr, 32 patients had a recurrence. Assuming a cutoff level for Tg1 at 0.27 ng/ml, Tg1 sensitivity and specificity reached 72 and 86%, respectively, whereas predictive positive and negative values were 20 and 99%, respectively. With a cutoff level for Tg2 at 1.4 ng/ml, sensitivity and specificity reached 78 and 90%, respectively, whereas positive and negative predictive values were 26 and 99%, respectively. CONCLUSION: This large prospective cohort of patients presented a low rate of recurrence. Initial Tg measurements allow to predict long-term recurrence with an excellent specificity. Stimulated Tg determination presented a slightly higher sensitivity than Tg determination on LT4. TSH stimulation may be avoided when Tg measured 3 months after ablation is less than 0.27 ng/ml during LT4 treatment.

Skeletal involvement in adult patients with endogenous hypercortisolism.

Overt endogenous glucocorticoid excess is a well-recognized cause of bone loss and osteoporotic fractures. Cortisol excess inhibits bone formation, increases bone resorption, impairs calcium absorption from the gut, and affects the secretion of several hormones (in particular gonadotropins and GH), cytokines, and growth factors, influencing bone metabolism. The glucocorticoid excess mainly affects trabecular bone, leading to vertebral fractures in up to 70% of patients. Osteoporotic fractures may be the presenting symptom of an otherwise silent glucocorticoid excess and can precede the diagnosis of hypercortisolism by up to 2 yr. The removal of glucocorticoid excess leads to a recovery of bone mass which is, however, often incomplete and delayed, although it reduces the risk of osteoporotic fractures. Bisphosphonate therapy has been suggested to be useful in maintaining bone mass in these patients. Subclinical hypercortisolism, a condition of impaired hypothalamic- adrenal-axis homeostasis without the classical signs and symptoms of glucocorticoid excess, is a recently defined entity, which has been shown to be associated to increased bone resorption, bone loss, and high prevalence of vertebral fractures regardless of gonadal status. However, data about the effect of this subtle glucocorticoid excess on bone are still scarce and conflicting. Moreover, it is not yet known whether removing the cause of subclinical hypercortisolism leads to a recovery of bone mass and reduces the risk of osteoporotic fractures. Finally, recent data suggest that subclinical hypercortisolism is a common and underrated finding in patients with established osteoporosis. In summary, it is crucial to evaluate the risk of osteoporosis and fractures in patients with glucocorticoid excess; on the other hand, it also seems advisable to screen for glucocorticoid excess patients with osteoporotic fractures without known secondary causes of osteoporosis.

Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients.

BACKGROUND: Serum thyroglobulin (Tg) is the marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease. AIM: The goal of the study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T4 treatment and after TSH stimulation. METHODS: Thyroid cancer patients who had no evidence of persistent disease after initial treatment (total thyroidectomy and radioiodine ablation) were studied at 3 months on L-T4 treatment (Tg1) and then at 9-12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up. RESULTS: Thirty recurrences were detected among 944 patients. A control 131I total body scan had a low sensitivity, a low specificity, and a low clinical impact. Assuming a common cutoff for all Tg assays at 0.9 ng/ml, sensitivity ranged from 19-40% and 68-76% and specificity ranged from 92-97% and 81-91% for Tg 1 and Tg2, respectively. Using assays with a functional sensitivity at 0.2-0.3 ng/ml, sensitivity was 54-63% and specificity was 89% for Tg1. Using the two methods with a lowest functional sensitivity at 0.02 and 0.11 ng/ml resulted in a higher sensitivity for Tg1 (81% and 78%), but at the expense of a loss of specificity (42% and 63%); finally, for these two methods, using an optimized functional sensitivity according to receiver operating characteristic curves at 0.22 and 0.27 ng/ml resulted in a sensitivity at 65% and specificity at 85-87% for Tg1. CONCLUSION: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T4 treatment and may be used to study the trend in serum Tg without performing any TSH stimulation. Serum Tg determination obtained after TSH stimulation still permits a more reliable assessment of cure and patient's reassurance.

Global skeletal uptake of 99mTc-methylene diphosphonate (GSU) in patients affected by endocrine diseases: comparison with biochemical markers of bone turnover.

This study aimed to clinically validate the global skeletal uptake (GSU) of (99m)Tc-methylene diphosphonate ((99m)Tc-MDP), and to compare it with a marker of bone formation (i.e. serum osteocalcin or OC) and an index of bone resorption (i.e. urinary deoxypyridinoline or U-DPD) in different endocrine disorders affecting the skeleton. We studied 29 female patients with thyrotoxicosis (TT), 27 with primary hyperparathyroidism (PHPT), 16 with acromegaly (AC), 15 with Cushing's syndrome (CS), and altogether 110 healthy women matched for age, BMI and menstrual status. In all subjects total body digital scan images (TBDS) were acquired at 5 min and at 4 h after the administration of (99m)Tc-MDP; the whole body retention (WBR) of the tracer was measured by counting two identical sets of rectangular ROIs, and GSU was subsequently calculated by drawing an irregular ROI on 4 h TBDS images. Serum OC was assessed by IRMA and urinary DPD by fluorometric detection after reverse phase high pressure chromatography. In TT patients GSU (40.0 +/- 5.1 vs 36.5 +/- 4.8%), OC (19.1 +/- 11.8 vs 7.1 +/- 2.9 microg/l) and U-DPD (62.4 +/- 42.7 vs 19.5 +/- 5.3 pmol/pmol) were significantly ( p<0.01) higher than in controls. PHPT patients showed GSU (47.2 +/- 6.6 vs 37.8 +/- 5.3%), OC (38.6 +/- 40.9 vs 8.2 +/- 2.5 microg/l), and U-DPD (55.0 +/- 51.3 vs 21.9 +/- 6.1 pmol/pmol) values significantly ( p<0.001) higher than controls. In CS patients, GSU (39.6 +/- 6.4 vs 32.7 +/- 3.5%; p<0.01) and U-DPD (22.8 +/- 8.4 vs 16.5 +/- 2.7 pmol/pmol; p<0.05) were higher, whereas OC (3.6 +/- 2.4 vs 5.2 +/- 1.9 mg/l; p<0,05) was lower than in controls. In AC patients, GSU (34.9 +/- 5.3 vs 35.2 +/- 3.4%) did not differ significantly from controls, whereas OC (16.8 +/- 8.8 vs 6.9 +/- 2.9 microg/l; p<0.001) and U-DPD (30.9 +/- 13.6 vs 21.0 +/- 5.7 pmol/pmol; p<0.01) were higher. Stepwise multivariate linear regression analysis was performed with disease activity, creatinine clearance, age, and years since menopause as predictor variables and GSU or OC or U-DPD as dependent variables. The significant partial regression coefficients ( r) were: in TT, free triiodothyronine (fT3) with GSU ( r = 0.37; p<0.005), Ln OC ( r = 0.30; p = NS), Ln U-DPD ( r = 0.76; p<0.0001), respectively; in PHPT, PTH with GSU ( r = 0.74; p<0.001), Ln OC ( r = 0.50; p<0.05), Ln U-DPD ( r = 0.64; p<0.001); in CS Ln urinary free cortisol with OC ( r = -0.68; p<0.001) and U-DPD ( r = 0.66; p<0.05). Our data suggest that GSU could represent a valuable clinical tool for evaluating bone turnover rate in PHPT, CS, TT but not in AC. The behavior of GSU and OC and U-DPD is non-uniform in disorders characterized by a marked uncoupling between bone formation and resorption.

Bone loss rate in adrenal incidentalomas: a longitudinal study.

Although by definition patients with adrenal incidentalomas (AI) do not have evident clinical syndromes, they may frequently suffer from subclinical hypercortisolism (SH). This is of some importance because of evidence that SH may lead to clinical complications, including bone loss. Thus, the understanding of bone involvement due to SH may be extremely important in the management of AI. Unfortunately, the available data on bone mineral density (BMD) in AI patients come from cross-sectional studies, which, to further complicate our understanding, are also conflicting, probably due to a different selection of patients and/or the variability in cortisol secretion (CS) often described in AI. To gain further insight about this topic, we performed a longitudinal study evaluating the rate of spinal and femoral bone loss levels in 24 females with AI. AI subjects were subdivided in two groups on the basis of the median of urinary cortisol secretion (UFC): group I (n = 12; UFC, <140.4 nmol/24 h) and group II (n = 12; UFC, >140.4 nmol/24 h). Spinal BMD was measured by both single energy quantitative computed tomography (L1-L4) and dual energy x-ray absorptiometry (DXA; L2-L4), and femoral BMD was determined by DXA. Bone loss rate was expressed as the change in z-score per yr. The spinal bone loss rate was higher (P < 0.005) in group II than in group I when measured by both quantitative computed tomography (-0.19 +/- 0.14 vs. 0.00 +/- 0.15) and DXA (-0.19 +/- 0.17 vs. 0.00 +/- 0.11). Moreover, CS and spinal bone loss rate were significantly correlated when patients were considered together. In conclusion, our data show that 1) AI patients with higher CS have increased lumbar trabecular bone loss rate than those with lower CS; and 2) the degree of spinal bone loss rate is related to the degree of CS. Thus, lumbar spine (LS) BMD has to be evaluated for well balanced decision-making on the treatment of choice for AI female patients.

Radioiodine and percutaneous ethanol injection in the treatment of large toxic thyroid nodule: a long-term study.

Surgery is generally recommended for large thyroid toxic nodules (TTNs). When surgery is not applicable, both radioactive iodine (RAI) and percutaneous ethanol injection (PEI) are alternative treatments. In this retrospective study, the long-term efficacy of nonsurgical treatments was evaluated in 43 patients with TTN, selected on the basis of presence of hyperthyroidism and a fairly large nodule (3- and 4-cm in diameter) completely inhibiting controlateral lobe captation during scintigraphy. Twenty-one patients were treated by RAI (administered dose 670+/-160 MBq; range 555-925) and twenty-two were treated by PEI (6+/-1 sessions; range 5-9). FT4, FT3, thyrotropin (TSH), and nodule volume were assessed before and at fixed intervals after treatment. Median follow-up was 36 months (range, 12-84). Compared to baseline values, with both therapies, serum FT4, FT3, and nodule volume were decreased (p < 0.01) and serum TSH was increased (p < 0.01), after 3 months and during the entire follow-up. Nodule volume reduction percentage was 66.8+/-22.0 and 78.4+/-18.0, in the RAI- and PEI-treated groups, respectively. At the end of follow-up, 34 patients were euthyroid (16 RAI- and 18 PEI-treated). Four RAI-treated patients (19%) showed slightly high TSH levels (4.2-5.3 mU/L), whereas three PEI-treated patients (13.6%) still had suppressed TSH levels, although being clinically asymptomatic. One RAI-treated patient (4.8%) showed overt hypothyroidism during the follow-up period and was then treated with L-thyroxin. One patient (4.6%), who was initially cured by PEI, became newly hyperthyroid during the follow-up period. Both treatments were well-tolerated. In conclusion, both of these nonsurgical treatments are effective and may be chosen also for relatively large TTNs. Specifically, RAI seems to be more effective for treating hyperthyroidism but has minimal sequelae of subclinical or clinical hypothyroidism, while, after PEI treatment the possibility of stable subclinical hyperthyroidism or hyperthyroidism relapse should be taken into account.

Age-related changes assessed by peripheral QCT in healthy Italian women.

The purpose of this study was to describe the normal cross-sectional pattern of radial bone loss associated with aging in healthy women and to generate a normative database using peripheral quantitative computed tomography (pQCT). Subjects with suspected conditions affecting bone metabolism or receiving any drugs affecting bone mineralization were excluded. The trabecular bone mineral density (BMD) and the total bone density of the ultradistal radius at the nondominant forearm was measured using the Norland-Stratec XCT-960 pQCT scanner in 386 healthy pre-, peri-, and postmenopausal females aged 15-81 years. The long-term in vivo precision error was 1.6 % CV (coefficient of variation) for trabecular and 0.8% CV for total BMD measurements. The highest value of trabecular and total BMD measured was observed at the age group 15-39 years. Beyond these ages both trabecular and total BMD showed a linear decline with aging, decreasing by an overall slope of -1.28 and -0.55 mg/cm3 per year for total and trabecular BMD measurements, respectively. The test of parallelism between the regression slopes of the peri- and postmenopausal women showed a statistically significant difference for total BMD measurement (p = 0.003). Measurement of total and trabecular BMD was not influenced by weight, height or body mass index, but it was correlated with natural logarithm of years since menopause. We conclude that pQCT of the ultradistal radius is a precise method for measuring the true volumetric BMD and for detecting age-related bone loss in the trabecular and total bone of female subjects encompassing the adult age range and menopausal status.

Percutaneous ethanol injection may be a definitive treatment for symptomatic thyroid cystic nodules not treatable by surgery: five-year follow-up study.

We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment for thyroid cystic nodules. Among patients referred for symptomatic thyroid cystic nodules who had relapsed after two aspirations or whose nodules could not be aspirated due to the thickness of the cystic fluid, PEI was given when surgery was either refused or contraindicated. Forty-three patients were treated; the mean basal volume of the cysts was 38.4 mL. The purpose of the study was to evaluate long-term efficacy of PEI treatment on: (1) amelioration of symptoms and signs of local compression and (2) nodule volume reduction. In three subjects (7%), PEI failed to induce a significant (>50%) nodule reduction, so that surgical treatment was performed. In 40 patients (93%), an impressive nodule shrinkage was observed, reaching a plateau after 24 months (volume reduction = 91.9%+/-11.4%). A new PEI session was needed in two patients in whom a recurrence was noted within the first 6 months. After 6 months, no significant (> or =1 mL volume) nodule regrowth was observed up to 60 months. Both symptoms and tracheal displacement rapidly (within 1 month) and significantly (p<0.01) improved. After PEI, mild pain was the only side effect observed. No suspicious cytology was observed in any residual nodule greater than 1 mL 6 and 24 months after the last PEI session. Our data suggest that PEI is a first-line safe, effective, probably definitive, treatment for cystic thyroid nodules for which surgery is either refused or contraindicated.

Altered bone mass and turnover in female patients with adrenal incidentaloma: the effect of subclinical hypercortisolism.

The strategy of treatment for patients with adrenal incidentalomas (AI) may depend upon the presence of hormonal hypersecretion. Although alterations of bone turnover have been recently reported, data on bone mineral density (BMD) are not available in AI patients. We evaluated bone turnover and BMD in 32 female AI patients and 64 matched controls. Spinal and femoral BMD were similar in patients and controls. Serum bone GLA protein (6.8+/-3.5 vs. 8.8+/-3.2 ng/mL; P<0.005) and PTH (48.8+/-15.1 vs. 37.2+/-10.9 pg/mL; P<0.0001) were different in patients and controls. Patients were then subdivided into 2 groups: with (n = 8; group A) or without (n = 24; group B) subclinical hypercortisolism. PTH was higher (P<0.05) in group A than in group B and in both groups than in controls (57.1+/-13.6, 46.0+/-14.8, and 37.2+/-10.9 pg/mL, respectively), and bone GLA protein was lower in group A than in group B and controls (3.8+/-2.3, 7.5+/-3.1, and 8.8+/-3.2 ng/mL, respectively; P<0.05). Serum type I cross-linked C telopeptide and fasting urinary deoxypyridinoline/ creatinine were not different in the three groups. BMD at each site was lower (P<0.05) in group A than in group B and controls. Bone mass and metabolism are altered in AI patients with subclinical hypercortisolism and should be taken into account, therefore, when addressing the treatment of choice for these patients.

Alterations of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing's syndrome.

The aim of the present investigation was to study the effect of glucocorticoid excess on bone mass and turnover not influenced by other diseases known to affect skeleton and/or by different gonadal status and sex. We studied several markers of bone turnover and bone mineral density (BMD) by both quantitative computed tomography (at spine and forearm) and dual x-ray absorptiometry (at spine and three femoral sites) in 18 eugonadal female patients affected by Cushing's syndrome (CS) compared to 24 eugonadal healthy female subjects matched for age and body mass index. In CS patients, serum bone Gla protein, a marker of osteoblastic function, was reduced (3.28 +/- 2.3 vs. 6.47 +/- 2.5; P < 0.01), and bone resorption was increased, as indicated by increased urinary hydroxyproline (36.6 +/- 12 vs. 29.0 +/- 9.1, P < 0.05) and urinary deoxypyridinoline (22.1 +/- 8.0 vs. 16.4 +/- 6.3; P < 0.05). BMD was significantly (P < 0.05 or P < 0.01) reduced at all sites, except cortical forearm, in CS patients compared to controls. By comparing z-scores of reduced BMD in CS patients, spinal trabecular BMD was found to be the most severely affected. Furthermore, disease activity, as measured by urinary free cortisol, was significantly correlated with bone Gla protein (r = -0.57; P < 0.02), urinary hydroxyproline (r = 0.57; P < 0.02), urinary deoxypyridinoline (r = 0.48, P < 0.05), and BMD measured at spine and femur. Our results show that compared to matched control subjects, female eumenorrheic CS patients have reduced osteoblastic function, increased bone resorption, and reduced BMD, and that the severity of these abnormalities is statistically related to the severity of disease activity, as indicated by urinary free cortisol. Moreover, our data suggest a site and tissue specificity of the effect of glucocorticoid excess on bone mass.

Pre-Cushing's syndrome not recognized by conventional dexamethasone suppression-tests in an adrenal "incidentaloma" patient.

Pre-Cushing's syndrome has been recently diagnosed in 6-12% of patients affected with incidentally discovered adrenal masses. Some of these patients have been described to show transient hypoadrenalism after surgery, similarly to those affected with overt Cushing's syndrome. We studied a 70-year-old male patient with a large left adrenal mass, incidentally discovered, who displayed 24-h urinary free cortisol levels at the upper limit of the normal range, normal dexamethasone overnight and low-dose suppression tests and not suppressed ACTH levels, increased 17-hydroxyprogesterone response to ACTH stimulation and low upright plasma renin activity with normal serum aldosterone levels; furthermore, DHEAS level was low and 75 Selenium-cholesterol scintigraphy showed unilateral uptake concordant with the side of the mass. Soon after left adrenalectomy, he complained of acute hypoadrenalism requiring cortisol replacement therapy: ten months after surgery he is still hypoadrenal. Moreover, stimulated 17-hydroxyprogesterone and plasma renin activity in clino- and orthostatic posture have become normal. We propose that conventional dexamethasone suppression-tests may be not enough sensitive in this kind of patients and that in selected cases the absence of controlateral uptake at scintigraphy may be more reliable in predicting post-surgical hypoadrenalism.

Percutaneous ethanol injection of large thyroid cystic nodules.

To evaluate the effect of percutaneous ethanol injection (PEI) in the treatment of large compressive thyroid cystic nodules (TCN), we studied 20 patients, potential candidates for surgery (tracheal displacement, nodule volume over 10 mL at ultrasonography) and not cured by aspiration alone: 14 experienced a recurrence after two complete evacuations of cystic fluid (watery nodules, WN); in six an aspiration was impossible because the cystic fluid was very thick (viscous nodules, VN). To exclude malignancy, both cytocentrifugate from WN and the smears from VN were examined. WN were treated with 1-4 sessions of conventional PEI; in VN a first PEI session was performed with the purpose of reducing the density of cystic fluid; then if cystic fluid was successfully aspirated, one or more PEI sessions were performed. Thyroid palpation, ultrasonography with nodule volume assessment, and assays for FT3, FT4, and TSH were performed 1 and 6 months after the last PEI. At month 6, 17 patients (85%) had volume reduction of more than 90% of the initial nodule volume; in 2 patients (10%) there was a reduction between 50 and 90%, and in one patient (5%) an appreciable swelling persisted after 3 injections. Nodule volume was significantly decreased below baseline at month 1 (10.9 +/- 13.3 vs 39 +/- 24 mL, p < 0.001), with a further reduction at month 6 (5 +/- 11.7 mL, p < 0.01 vs 1st month value). In most of the nodules the cystic portion completely disappeared; the residual tissue showed fibrous features, often with calcifications. In 11 patients follow-up was prolonged over the sixth month (15 +/- 4 months); the nodule volume did not significantly differ from the sixth month (3 +/- 2.2 mL) and the end of the follow-up (2.8 +/- 2.3 mL). In conclusion, we demonstrate that PEI may be a safe and effective procedure in the treatment of large TCN.

Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

OBJECTIVE: A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. DESIGN: Longitudinal prospective study of previously untreated patients with GD. PATIENTS: Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. MEASUREMENTS: Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. RESULTS: Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. CONCLUSIONS: Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.

A thyroid hormone receptor beta gene polymorphism associated with Graves' disease.

Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n = 120) from the same area was also analysed. The distribution of EA beta H alleles was significantly different (P < 0.001) in Graves' disease (n = 94) but not in autoimmune thyroiditis (n = 60), as compared with controls. Also the distribution of the EA beta H genotypes was significantly different in Graves' patients (P = 0.003), as compared with controls, the homozygous state EA beta H+/EA beta H+ being more frequent in Graves' patients than in all the other groups. We did not find any association between EA beta H genotypes and clinical parameters in Graves' patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves' disease is a genetically distinct group within the AITDs.

[Unusual endocrine behavior in adrenal carcinoma. A case study]. / Insolito comportamento endocrino di carcinoma surrenalico. Studio di un caso.

The Authors report a case of left adrenal mass incidentally discovered by upper abdominal echogram in a 40 year old man. Physical examination showed no signs of hypercortisolism and plasma cortisol and ACTH levels were in the normal range as well as urinary free cortisol. After adrenalectomy, 4 and 8 month follow-up was performed, without clinical, hormonal and TC evolution. Thirteen months later the patient was referred to our department for widespread oedema, hypertension, hypokalemia and alkalosis. These symptoms were associated with dramatically elevated concentrations of plasmatic and free urinary cortisol. TC showed a large mass in the same adrenal region and diffuse hepatic metastases. In spite of mitotane and ketoconazole therapy the patient died few weeks later.

Hypoechoic focal liver lesions in granulomatous hepatitis and hemochromatosis.

Hypoechoic focal liver lesions are described, for the first time, in two patients with granulomatous hepatitis and hemochromatosis, and presenting a 'bright liver pattern' at ultrasonography. CT-scan was not able to make evident such areas in both cases, while hepatoscintigraphy revealed them only in the patient with granulomatous hepatitis. Echoguided fine-needle biopsies on the focal lesions were suitable for the correct final diagnoses. The finding of such areas was probably due to different intensity of the diseases in contiguous zones of liver parenchyma.

Evaluation of pituitary-thyroid axis response to acute myocardial infarction.

We have studied with seriated controls for a period of 9 days 18 patients admitted to our hospital for acute myocardial infarction (AMI). Slight, but non significant variations in thyroidal hormone pattern were observed: slight decrease of T3 and T4 levels, increase of reverse T3 on day 3, low free T4 levels, slight increase of TSH levels until the 3rd day. However, hormonal pattern was clearly different in patients who presented a clinical improvement (group 1a) and in patients who died for AMI (group 1b). In fact, a significant TSH increase was recorded in patients of group 1a; on the contrary, a significant decrease of TSH, T4 and free T4 concentrations was observed for subjects of group 1b, suggesting an inadequate response of pituitary-thyroid axis. In conclusion, the evaluation of thyroid hormones and thyrotropin levels can be of clinical usefulness in the management of patients with AMI. The decrease of plasma T4 and free T4 concentrations, accompanied with low TSH levels, can be associated with unfavorable course of the disease and therefore can be considered a bad prognostic sign.

Differential effects of a dopaminergic drug (piribedil) on pituitary hormone release in normal men and women.

Six normal women, in the follicular phase of their menstrual cycle, and 6 normal men received orally 40, 60 and 100 mg doses of piribedil, a dopamine receptor agonist, or placebo. The effects of piribedil on anterior pituitary hormone release was evaluated. In normal women a dose-related decrease in Prl levels was observed, while in men the Prl decrement was not related to the dose employed. In women an increase in serum hGH occurred after administration of the lowest (40 mg) dose of piribedil. In normal men, on the contrary, a modest hGH stimulation was present after administration of all doses of the drug. No consistent changes in serum TSH, LH and FSH concentrations were observed and no side effects were reported. The results from this study indicate that piribedil can exert differential effects on hypophyseal trophic hormone release and that these effects are sex-related. It is possible that the differences observed in men and women after the administration of piribedil are due to a different endogenous dopaminergic tone, induced by the different sexual steroid environment.