Thalassemic osteopathy: a new marker of bone deposition.

Osteopathy represents a prominent cause of morbidity in patients with beta-thalassemia major (TM) and manifests as osteopenia/osteoporosis. Biochemical turnover markers (BTMs) are considered a useful, non-invasive tool for the clinical follow-up of osteoporotic patients; they can provide a dynamic view of the remodeling process and give information on the metabolic activity of bone tissue as well as on the pathogenesis of bone loss. The amino-terminal pro-peptide of type I procollagen (P1NP) is a recently introduced marker that is considered the most sensitive index of bone formation. Although demonstrated in several categories of patients with bone disease, there is little information on the clinical usefulness of this bone formation index in thalassemic patients. We evaluated the P1NP levels of 53 adult patients with b-thalassemia major (21 males and 32 females, mean age 34.5 ± 5.7, range 22-46 years) and associated osteopathy. We investigated the correlation between P1NP and bone condition as examined by dual X-ray photon absorptiometry and with BTMs expressing bone resorption and bone mineralization (carboxyterminal collagen cross-linked (CTX) terminal regions of type I collagen and osteocalcin, respectively). P1NP serum levels were correlated with CTX levels (r=0.545, p<0.001); the results were unchanged when males and females, as well as osteoporotic and osteopenic subgroups, were considered separately. No correlation was demonstrated neither between OC and CTX (r=0.17, p=ns), nor between P1NP and OC levels (r=0.11, p=ns). No correlation was demonstrated among the P1NP/CTX ratio and age, OC or densitometric values and no difference was found in the same ratio between osteopenic (0.19 ± 0.16) and osteoporotic (0.15 ± 0.14) patients. Similar results were obtained for the OC/CTX ratio, as it was not correlated with age, P1NP or densitometric values. This is the first report of circulating P1NP in patients with TM-associated osteoporosis. P1NP and CTX assays show good precision and low analytical CV, and, compared to other markers, they can acceptably reflect bone metabolic processes and promptly respond to antiosteoporotic treatments. We trust that this sensitive marker can be useful in the assessment of treatment efficacy and can overcome the pitfalls due to wide variability in the normal values of most BTMs that create difficulty in pinpointing the individual patient's response.

A comparison between metabolic syndrome post-hematopoietic stem cell transplantation and spontaneously occurring metabolic syndrome.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is used in the treatment of several hematological and non-hematological disorders. An increasing number of long-term survivors recover from their primary disease, but they are at risk of adverse late effects, including metabolic syndrome (MS), which seems to be common in long-term survivors of HSCT. AIM: To compare common metabolic parameters and adipohormone profiles in post-transplant and spontaneously occurring or "classic" MS patients. SUBJECTS AND METHODS: Post-transplant MS patients (15 women and 14 men; 49.8±9.3 yr) were compared to "classic" MS patients (15 women and 14 men; 52.9±8.0 yr). For each subject a record of conventional clinical parameters was made; moreover, serum leptin, insulin, quantitative C-reactive protein (CRP), tumor necrosis factor-α [TNF-α], and adiponectin concentrations were measured. RESULTS: The patients with post-HSCT MS had significantly higher levels of leptin, CRP, and TNF-α than the patients with "classic" MS. A generalized linear model comprising serum insulin (p=0.022), body mass index (p<0.001), gender (p<0.001), and group (i.e. healthy, post-HSCT with MS, or suffering from "classic" MS; p<0.001) explained serum leptin variability (adjusted R(2)=0.741). Serum leptin concentrations and BMI were related in the patients with "classic" MS but not in those with post-HSCT MS. CONCLUSIONS: A possible pathogenetic mechanism in the development of MS after HSCT could be hyperleptinemia. A potential interaction among circulating leptin, components of MS, and immune function might explain the role of this adipokine in mediating cardiovascular risk after HSCT.

Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation.

Our purpose was to determine the prevalence and features of metabolic syndrome (MS) in a series of long-term hematopoietic stem cell transplantation (HSCT) survivors. We assessed the clinical, metabolic and endocrinological data, and plasma TNF, leptin, resistin and adiponectin levels relating to 85 HSCT recipients. MS was diagnosed on the basis of the National Cholesterol Education Program-Adult Treatment Panel III criteria. Its prevalence was compared with that observed in an Italian population, and its relationship with the clinical and laboratory parameters was assessed univariately and multivariately. Twenty-nine HSCT recipients had MS instead of the 12.8 expected (P<0.0001), with hypertriglyceridemia being the most common feature. Univariate analysis indicated that high insulin and leptin levels, low-adiponectin levels and hypogonadism were significantly related to a diagnosis of MS; multivariate analysis indicated plasma leptin, insulin resistance, age and hypogonadism. We conclude that HSCT recipients are at increased risk of a form of MS that has particular clinical features. Plasma leptin levels are independently related to MS, thus suggesting that leptin resistance may play a role as a pathogenetic clue, as in other conditions in which MS occurs as a secondary phenomenon. MS deserves consideration as a life-threatening complication in patients who are probably cured of their underlying disease.

Treatment of benign nodular goitre with mildly suppressive doses of L-thyroxine: effects on bone mineral density and on nodule size.

OBJECTIVES: To evaluate (i) the demineralizing effect of L-thyroxine (LT4) therapy at doses mildly inhibiting serum thyroid stimulating hormone (TSH) in patients with benign nodular goitre; (ii) the efficacy of treatment on nodule size. DESIGN: Cross-sectional study comparing euthyroid women with nodular goitre treated with LT4 for > or = 2 years (52 +/- 32 months, range 24-138, median 42) and a matched group with untreated goitre. SUBJECTS: A total of 89 female outpatients (53.3 +/- 9 years; 36 pre- and 53 postmenopausal), 43 treated and 46 untreated. MAIN OUTCOME MEASURES: Bone mineralization was measured with total body and regional mineralometry [dual energy X-ray absorptiometry (DEXA)], and indirectly evaluated with biochemical parameters (alkaline phosphatase, osteocalcin). Efficacy of LT4 therapy was assessed by measuring the nodule size during ultrasonography. The adequacy of the treatment was evaluated on the basis of serum TSH levels. RESULTS: No significant differences were found at DEXA for total body and regional mineralization (P > 0.05 for all comparisons) in treated and untreated patients, both in pre- and postmenopausal states. Evaluation of the nodule size during the ultrasound scan showed a reduction of > or = 30% in 11 of 43 treated patients (26%) versus none of the untreated, an unchanged size in 29 treated patients (67%) versus 18 untreated, an increase of nodules and/or new nodule development in three treated patients (7%) versus 28 untreated (61%). CONCLUSIONS: L-thyroxine (LT4) treatment at doses slightly suppressing TSH does not significantly affect bone mineralization, nor does it represent a risk factor for osteoporosis, even in postmenopausal patients. The efficacy of this therapeutic schedule on goitre size is comparable with the effects previously reported with suppressive doses.

Dynamics of a nosocomial outbreak of multidrug-resistant Pseudomonas aeruginosa producing the PER-1 extended-spectrum beta-lactamase.

From November 1998 to August 1999, a large outbreak occurred in the general intensive care unit of the Ospedale di Circolo in Varese (Italy), caused by Pseudomonas aeruginosa producing the PER-1 extended-spectrum beta-lactamase. A total of 108 clinical isolates of P. aeruginosa resistant to broad-spectrum cephalosporins were recovered from 18 patients. Epidemic isolates were characterized by synergy between clavulanic acid and ceftazidime, cefepime, and aztreonam. Isoelectric focusing of crude bacterial extracts detected two nitrocefin-positive bands with pI values of 8.0 and 5.3. PCR amplification and characterization of the amplicons by restriction analysis and direct sequencing indicated that the epidemic isolates carried a bla(PER-1) determinant. The outbreak was of clonal origin as shown by pulsed-field gel electrophoresis analysis. This technique also indicated that the epidemic strain was not related to three other PER-1-positive isolates obtained at the same hospital in 1997. Typing by enterobacterial repetitive intergenic consensus-PCR showed that minor genetic variations occurred during the outbreak. The epidemic strain was characterized by a multiple-drug-resistance phenotype that remained unchanged over the outbreak, including extended-spectrum cephalosporins, monobactams, aminoglycosides, and fluoroquinolones. Isolation of infected patients and appropriate carbapenem therapy were successful in ending the outbreak. Our report indicates that the bla(PER-1) resistance determinant may become an emerging therapeutic problem in Europe.

Thyroid nodules in Graves disease and the risk of thyroid carcinoma.

BACKGROUND: The risk of thyroid carcinoma in patients with Graves disease has been particularly emphasized when nodules coexist with thyroid hyperplasia; a surgical approach has been suggested. OBJECTIVES: To detect thyroid nodules early in patients with Graves disease and to evaluate the risk of carcinoma. METHODS: The study group included 315 consecutive outpatients with Graves hyperthyroidism not previously treated with surgery or radioiodine therapy. Thyroid ultrasonography was performed at the time of enrollment and repeated annually in all patients; fine-needle aspiration (FNA) was carried out in those patients with nodules and repeated after 2 years or at shorter intervals. RESULTS: One hundred six of 315 patients with Graves disease had thyroid nodules 8 mm in diameter or larger detected by ultrasonography. In 49 patients, nodules were present at the time of the first examination; in 57 patients, nodules developed during follow-up. Fine-needle aspiration cytology results revealed features of carcinoma in only 1 patient; this was confirmed by histologic examination of excised thyroid tissue. The nodules with normal cytologic features at the time of the first examination did not show any clinical and/or cytologic evolution toward malignancy during follow-up. CONCLUSIONS: Ultrasonographic evidence of nodules was frequently found among our patients with Graves disease, but malignant FNA cytologic findings of the examined nodules were rare at the time of diagnosis and throughout the course of the disease. When FNA cytologic evaluation does not indicate malignancy, the presence of thyroid nodules in patients with Graves disease does not indicate an aggressive therapeutic approach.

Pattern of plasma cyclic nucleotides and related hormones in liver cirrhosis and hepatocellular carcinoma.

To evaluate the pattern of plasma cyclic adenosine 3',5'-monophosphate, cyclic guanosine 3',5'-monophosphate, atrial natriuretic factor and glucagon levels in different stages of chronic liver diseases, we measured these variables in 20 normal subjects, 25 patients with genetic hemochromatosis, associated with liver cirrhosis in 19 cases and not in six, eight patients with compensated and 15 with decompensated alcoholic or posthepatitic cirrhosis, and 12 with hepatocellular carcinoma. All variables were within the normal range in non-cirrhotic hemochromatotic patients. Cyclic adenosine 3',5'-monophosphate levels were within the normal range (9.5-15.7 nmol/l) in hemochromatotic cirrhotics and elevated in other patients. Cyclic guanosine 3',5'-monophosphate, atrial natriuretic factor and glucagon were above the normal ranges (1.92-5.91 nmol/l, 8.8-62.7 ng/l, and 39-165 ng/l, respectively) in most patients with cirrhosis both with and without hemochromatosis and in most individuals with hepatocellular carcinoma. Cyclic guanosine 3',5'-monophosphate correlated with atrial natriuretic factor in the former groups but not in the latter. These findings indicate that glucagon and atrial natriuretic factor hypersecretion is an early event in cirrhosis, regardless of its etiology. In hepatocellular carcinoma, the underlying cirrhosis may account for most hormonal and metabolic changes although cyclic guanosine 3',5'-monophosphate increases could also be due to the neoplastic process per se.

Potentiating effect of galanin on GHRH-induced GH release. Comparison between old and young subjects.

The aim of our study was to investigate the effect of galanin on basal and GHRH-stimulated GH secretion in a healthy group of elderly subjects and in a healthy group of young subjects for comparison. Ten old subjects (mean age 75 +/- 1.15 years) and an equal number of healthy young volunteers (mean age 26 +/- 0.71 years) underwent three stimulation tests in random order. Galanin infusion for 60 minutes (10 micrograms/kg in 100 ml saline) failed to provoke an appreciable release of circulating GH in old subjects, while it induced a significant increase of plasma GH in the young adults; GHRH administration i.v. in bolus (100 micrograms in 1 ml saline) elicited a significant GH response in both groups; however, in the older group GH response was significantly (p < 0.05) lower than in the young adults. The administration of galanin (10 micrograms/kg in 100 ml saline as an i.v. infusion for 60 min) plus GHRH (100 micrograms in 1 ml saline i.v. in bolus), potentiated GH response in old and young subjects. The combined administration of two peptides was able to elicit a clear GH release even in the older subjects who were hyporesponsive/unresponsive to galanin and/or GHRH alone. In the elderly, plasma GH values observed after the combined stimuli overlapped with GH values observed after GHRH alone in the young adults. In conclusion, our study confirms that galanin has a synergic effect with GHRH on GH release both in younger and elderly subjects. Moreover, our data confirm an impaired responsivity to GHRH in the elderly and demonstrate that galanin is able to normalize response of somatotrophs to GHRH in old people.

The impact of long-term hemodialysis on pituitary-adrenocortical function.

The activity of the hypothalamic-pituitary-adrenal axis in hemodialyzed (HD) patients has been investigated, with conflicting results. Different results are reported concerning both basal ACTH and cortisol concentration and the responses to different stimulating agents, in chronic hemodialyzed patients. The present study was performed in order to asses whether the length of the hemodialytic treatment may affect the pituitary and adrenocortical response to stimulation with ovine CRH (oCRH) and with exogenous ACTH in a group of patients on chronic HD for more than 10 years. Ten uremic patients (aged 38-71, 6 males and 4 females) on chronic hemodialysis for at least 10 years and 7 healthy subjects matched for age and sex were studied. The patients were tested on the day preceding dialysis session. Each subject received on different non-consecutive days oCRH (100 micrograms i.v. in bolus) and ACTH (Synacthen 0.25 mg i.v. in bolus), and blood samples were obtained at appropriate intervals. Basal ACTH and cortisol levels of HD patients were in the upper limit of normal range (ACTH 39.21 +/- 11.11 pg/mL in HD patients vs. 26.88 +/- 14.12 pg/mL in controls; cortisol 19.96 +/- 5.07 in HD patients vs. 12.66 +/- 4.44 in controls); however, the means were not significantly different compared with controls. Following oCRH administration a net increase of ACTH and cortisol was observed in every patient tested (ACTH peak 83.81 +/- 28.49 in HD vs. 78.73 +/- 22.87 pg/mL in controls; cortisol peak 30.73 +/- 19.31 in HD vs. 20.05 +/- 3.19 micrograms/dL in controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Human lymphocyte antigens in Graves' disease: correlation with persistent course of disease.

Graves' disease is a thyroid autoimmune disorder associated with specific human lymphocyte antigen (HLA) alleles, characterized by an unpredictable long-term course. To investigate possible relations between HLA phenotype and outcome of the disease, the authors typed for HLA antigens in 105 patients with Graves' disease with different course of disease. All patients were treated with antithyroid drugs for at least 12 months; 29 patients had stable remission 24 or more months after withdrawal of treatment; 76 patients had persistent disease--66 unremitting/relapsing hyperthyroidism, 10 stable hypothyroidism--36 or more months after onset of disease. The following findings emerged from this study: 1) HLA B8 and DR3 were increased significantly in Graves' patients versus 6,682 control subjects from the same geographic area (23.80% vs 12.01%, odds ratio [OR] 1.98, and 31.43% vs 18.00%, OR 1.75, respectively); the antigen combinations B8-DR3, B8-Cw7-DR3, and A1-B8-Cw7-DR3 were significantly more frequent in Graves' patients vs control subjects; in addition, these combinations were present exclusively in patients with persistent disease (B8-DR3 28.95%, OR 7.14, B8-Cw7-DR3 27.63%, OR 11.24, and A1-B8-Cw7-DR3 18.42%, OR 11.29). These data provide evidence that not only susceptibility to Graves' disease, but also persistent activity of the autoimmune process, producing either hyperthyroidism or stable hypothyroidism, is associated with specific HLA antigen phenotypes.

Recombinant human erythropoietin (rhEPO) treatment potentiates growth hormone (GH) response to growth hormone releasing hormone (GHRH) stimulation in hemodialysis patients.

On the basis of previously described effects of recombinant human erythropoietin (rhEPO) treatment on endocrine abnormalities present in uremia, we assessed the possible effect of treatment with rhEPO on growth hormone (GH) response to growth hormone releasing hormone (GHRH) in a group of uremic patients. Eight patients on maintenance hemodialysis for 12 to 228 months, not previously treated with rhEPO, were tested with 100 micrograms of GHRH i.v. in bolus before and after three months of rhEPO treatment (40 U/kg i.v. three times a week). Before treatment, the GH response to GHRH was characterized, in uremic patients, by remarkable differences in plasma GH values and in the pattern of response curve in single patients. The variability of GH response was not modified after rhEPO treatment; however, an overall potentiation of GH response with a significant increase of plasma GH (p = 0.017 at 15 min, p = 0.035 at 30 min after GHRH injection) was observed in the tests performed after treatment. rhEPO administration induced an evident improvement of anemia, blood hemoglobin concentration being 5.3-7.6 g/dl before and 9.1-11.3 g/dl after treatment; however a demonstrable correlation between the potentiation of GH response to GHRH and the increase of hemoglobin concentration was not observed.

Reduction of insulin resistance after correction of nonneoplastic ovarian virilization.

A 60-year-old woman with a progressive virilization for about 5 yr developed diabetes mellitus with elevated insulin levels (fasting insulinemia ranging 32.4-45.8 microU/ml). The marked increase of plasma testosterone (total 5.7-8.2 ng/ml; free 11.5 pg/ml) and other endocrine markers clearly indicated the ovarian origin of hyperandrogenism. Pelvic ultrasonography, computerized axial tomography, and direct examination of ovaries during laparotomy, showed no evidence of neoplasia. Microscopic examination and immunocytochemical investigations confirmed the diagnosis of hyperthecosis. After oophorectomy and regression of hyperandrogenism, fasting and postprandial blood glucose concentrations normalized in spite of persistently elevated levels of insulinemia (fasting values ranging 32.0-61.0 microU/ml). The present case suggests that pathological increase of testosterone can interfere with insulin-glucose balance impairing the peripheral sensitivity to insulin.

Abnormal growth hormone responsiveness to stimuli in women with active celiac sprue.

Baseline somatomedin C (Sm-C) and responses of growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) to TSH-releasing hormone (TRH) and to L-dopa were evaluated in 10 untreated and nine treated women with celiac sprue, and in 10 normal women. Mean basal Sm-C, GH, PRL, and TSH levels were similar in all groups of subjects. In all subjects, L-dopa decreased PRL levels, without affecting TSH, and TRH increased PRL and TSH levels. In both controls and treated patients, TRH did not influence GH secretion, whereas L-dopa significantly increased GH levels. In untreated patients, GH levels paradoxically increased after TRH (8/10) but were unaffected by L-dopa (7/10). Because L-dopa would stimulate hypothalamic GH-releasing hormone (GHRH) secretion, four untreated patients, unresponsive to L-dopa, received GHRH, and GH levels rose markedly. These data suggest that, in untreated celiac sprue patients, hypothalamic control of GH secretion is reversibly impaired.

Inhibitory effect of somatostatin on abnormal GH response to TRH in primary hypothyroidism.

Thyrotropin releasing hormone (TRH) does not promote GH secretion in normal subjects but it stimulates GH in a proportion of hypothyroid patients. In this study the response of GH to thyrotropin releasing hormone (TRH) was evaluated in 21 patients with primary hypothyroidism of different origin: 12 with autoimmune thyroiditis, 3 idiopathic, 3 congenital, 3 iatrogenic. 11 of these patients had never been treated, the others were tested after a drug-free period of at least two weeks. Basal plasma concentration of GH was normal in all patients; after TRH administration, a significant increase in plasma GH was observed in 4 patients. In these responsive patients, somatostatin infusion inhibited the abnormal GH response to TRH. It is suggested that the abnormal GH response to TRH in primary hypothyroidism might be caused by a relative deficiency of somatostatinergic control, which is corrected by exogenous somatostatin administration.

Effect of chronic clonidine administration on GH secretion in adult human subjects.

It is well known that the acute administration of clonidine, an alpha 2-adrenergic agonist commonly used as an antihypertensive drug, stimulates GH secretion, likely via hypothalamic growth hormone releasing hormone (GHRH) release. Conversely, evidences of a hyperactivity of GHRH-GH-somatomedin C (SMC) axis during chronical administration of clonidine are controversial. In this study, GH and SMC levels have been evaluated in 16 hypertensive patients chronically treated with clonidine. The subjects were randomized to receive either TRH or saline with the aim of evaluating the non specific GH response to TRH as compared to spontaneous fluctuations during a control test. In basal conditions, GH and SMC concentrations in clonidine treated patients were similar to those observed in an age and sex matched group of normal untreated subjects. An abnormal increase in plasma GH occurred in 5 out of the 10 patients who received TRH, while plasma GH did not show significant variations during testing in the subjects who received saline. It is suggested that chronical administration of clonidine does not induce an hyperactivity of GHRH-GH-SMC axis as estimated by plasma GH and SMC concentrations, but may induce a disorder in hypothalamic control of GH secretion, possibly implicated in the abnormal GH responsivity to TRH.

Increased growth hormone response to growth hormone releasing hormone induced by erythropoietin in uraemic patients.

This study was designed to assess the response of growth hormone (GH) to growth hormone releasing hormone (GHRH) and the possible interaction of acutely administered recombinant human erythropoietin (rhEPO) on GH response to GHRH in a group of uraemic patients. Eight patients on maintenance haemodialysis, not previously treated with rhEPO, and six healthy controls were tested with GHRH (100 micrograms i.v. in bolus), and with GHRH (100 micrograms i.v. in bolus) plus rhEPO (40 U/kg in constant infusion for 30 min) on different days. GHRH injection provoked a GH release in five out of eight uraemic patients; the overall mean response did not differ significantly from the GH response obtained in controls (P = 0.30). Erythropoietin infusion significantly increased GH release after GHRH (P less than 0.01 at 15, 30, 45, 60 min after GHRH injection) in uraemic patients; in controls, on the contrary, stimulation with GHRH plus rhEPO did not induce a greater increase of GH release compared with that observed after GHRH alone (mean GH peak 37.66 +/- 7.68 mU/l after GHRH; and 38.0 +/- 9.18 mU/l after GHRH plus rhEPO; P greater than 0.5). In this study acutely administered rhEPO significantly potentiated the GH response to GHRH in uraemic patients whereas the same effect was not demonstrable in subjects with normal renal function.

CRH and lysine-vasopressin stimulation tests in the diagnosis of hypoadrenalism secondary to hypothalamic or pituitary disorders.

Ten patients with secondary hypoadrenalism have been tested with corticotropin releasing hormone (CRH) and lysine-vasopressin (LVP). One patient had isolated ACTH deficiency; 9 had deficiency of other pituitary hormones attributable to a primary pituitary disease in 3 and to an hypothalamic disorder in 6. After CRH administration, a definite increase in plasma ACTH was observed in all 6 patients with hypothalamic disorder. No response was elicited in the 3 patients with pituitary disease and in the patient with isolated ACTH deficiency. In the responsive patients. ACTH showed a delayed and prolonged pattern of response. Lysine-vasopressin administration produced an increase in plasma ACTH in 4 of the 6 hypothalamic patients and no response in those with pituitary disease and in the patient with isolated ACTH deficiency. These findings suggest that CRH represents a reliable test in differentiating hypothalamic from pituitary adrenal failure; LVP appeared a less sensitive diagnostic test.

Screening for non-classic 21-hydroxylase deficiency in an HLA-B14 positive population.

To evaluate whether HLA-B14 positive individuals are at increased risk for non-classic 21-hydroxylase deficiency, the response of progesterone and 17-hydroxyprogesterone to ACTH stimulation test was studied in a group of 27 apparently normal, HLA-B14 positive, blood donors. Four of these subjects showed a response typical of 21-hydroxylase defect. In the present series, the enzymatic defect was found to have a considerably lower prevalence than in a previous study of smaller size (15% vs 66%); however, considering the low frequency of the gene coding for the defect in the general population (0.015-0.057), the present results confirm an increased risk for non-classic 21-hydroxylase deficiency in HLA-B14 positive individuals. Therefore, in these subjects, a screening for 21-hydroxylase deficiency may be indicated.