Elena Passeri

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

OBJECTIVE A common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy. DESIGN Prospective study of GHD patients evaluated before and during short- (1 year, n=100) and long-term (5 years, n=50) rhGH therapy. METHODS Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant. RESULTS The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed. CONCLUSION The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

Large Pituitary Hyperplasia in Severe Primary Hypothyroidism

Endocrinology and Diabetology Unit (E.P., A.T., B.A., S.C.), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy; Department of Medical-Surgical Sciences (E.P., B.A., S.C.), University of Milan, 20097 San Donato Milanese, Milan, Italy; Department of Neurosurgery (M.L.), IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milano, Milan, Italy; and Endocrinology Unit (A.G.L.), Department of Medical Sciences, University of Milan, IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milan, Italy

Vitamin D, parathyroid hormone and muscle impairment in myotonic dystrophies

Parathyroid function in Myotonic Dystrophy (DM) patients has been poorly investigated. Parathyroid and muscle parameters were assessed in 31 male DM1 (44±2 years), 13 male DM2 (56±2 years) and 32 healthy controls. Hyperparathyroidism was diagnosed in 18% of patients without differences between DM types. In all DM patients, hyperparathyroidism was associated with normocalcemia but one with hypercalcemia. DM patients presented significantly higher PTH and lower vitamin D (25OHD) compared with controls, also considering seasonality. Severe vitamin D deficiency (25OHD<10 ng/ml) was diagnosed in 40% and hypovitaminosis D (25OHD<30 ng/ml) occurred in 88% of DM patients. About one-third of DM1 presented hypophosphatemia associated with elevated PTH levels. Serum 25OHD levels negatively correlated with PTH and with body fat mass. Considering DM1 patients, serum PTH levels positively correlated with CTG triplet repeats. Furthermore, PTH levels negatively correlated with total modified Medical Research Council (MRC) and positively with Muscular Impairment Rating Scale (MIRS). By contrast, in DM2 patients muscle assessment did not show any correlation with parathyroid function. In conclusion, we arrived at the following: 1) severe vitamin D deficiency is common in DM patients and it is associated with secondary hyperparathyroidism; 2) primary hyperparathyroidism, though rare, may occur; 3) increased adiposity in DM may be a risk factor for hypovitaminosis D; and 4) high serum PTH levels may indicate a muscle impairment, at least in DM1.

Increased Risk for Non-Autoimmune Hypothyroidism in Young Patients with Congenital Heart Defects

CONTEXT Newborns with congenital hypothyroidism (CH) have an increased risk for congenital heart defects (CHD) due to a common embryonic developmental program between thyroid gland and heart and great vessels. OBJECTIVE Our objective was to investigate the prevalence and origin of thyroid disorders in young patients with CHD. DESIGN AND SETTING We conducted a prospective observational study between January 2007 and January 2009 in academic Pediatric Cardiosurgery and Endocrinology. PATIENTS Patients included 324 children (164 males, 160 females, aged 0.2-15.4 yrs) with CHD. INTERVENTION Subjects underwent hormonal and genetic screening. MAIN OUTCOME MEASURES Serum TSH and thyroid hormone levels were assessed. RESULTS Two CHD patients were diagnosed with CH at the neonatal screening (1:162). Mild hypothyroidism (serum TSH > 4.0 μU/ml) was diagnosed and confirmed 6 months later [TSH = 5.4 ± 1.5 μU/ml; free T(4) = 1.3 ± 0.2 ng/dl (normal values 0.8-1.9)] in 37 children (11.5%) who were negative at neonatal screening. Hypothyroidism was not related to type of CHD, whereas TSH levels positively correlated with serum N-terminal pro-type B natriuretic peptide levels. Biochemical and ultrasound findings consistent with thyroid autoimmunity were present in three of 37 hypothyroid children (8.1%). One patient had hemiagenesis (2.7%). Variations in candidate genes were screened in CHD patients. NKX2.5 coding sequence was normal in all samples. A 3-Mb microdeletion in 22q11.2 was detected in three patients (8.3%), whereas only known polymorphisms were identified in TBX1 coding sequence. CONCLUSIONS CHD patients have an increased risk for both CH (10-fold higher) and acquired mild hypothyroidism (3-fold higher). Unrecognized mild hypothyroidism may negatively affect the outcome of CHD children, suggesting that thyroid function should be repeatedly checked. Thyroid autoimmunity and 22q11.2 microdeletions account for small percentages of these cases, and still unknown mechanisms underline such a strong association.

Desmopressin test may predict the risk of recurrence in Cushing's disease

1 Bartalena, L., Wiersinga, W.M., Tanda, M.L. et al. (2004) Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clinical Endocrinology , 61 , 494–502. 2 Tanda, M.L., Piantanida, E., Lai, A. et al. (2008) Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists. Clinical Endocrinology , 69 , 812–818. 3 Diehl, L.A., Romaldini, J.H., Graf, H. et al. (2006) Management of amiodarone-induced thyrotoxicosis in Latin America: an electronic survey. Clinical Endocrinology , 65 , 433–438. 4 Martino, E., Bartalena, L., Bogazzi, F. et al. (2001) The effects of amiodarone on the thyroid. Endocrine Reviews , 22 , 240–254. 5 Bartalena, L., Grasso, L., Brogioni, S. et al. (1994) Serum interleukin-6 in amiodarone-induced thyrotoxicosis. Journal of Clinical Endocrinology and Metabolism , 78 , 423–427.

Gonadal failure is associated with visceral adiposity in myotonic dystrophies

Hypogonadism occurs in myotonic dystrophies type 1 (MD1) and type 2 (MD2). Sertoli and Leydig cell secretions, including insulin‐like peptide‐3 (INSL3), anti‐Müllerian hormone (AMH) and inhibin B, were evaluated in male patients with MD.

A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation. Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women. Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test. Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks. Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients.

SNPs and real-time quantitative PCR method for constitutional allelic copy number determination, the VPREB1 marker case

Background22q11.2 microdeletion is responsible for the DiGeorge Syndrome, characterized by heart defects, psychiatric disorders, endocrine and immune alterations and a 1 in 4000 live birth prevalence. Real-time quantitative PCR (qPCR) approaches for allelic copy number determination have recently been investigated in 22q11.2 microdeletions detection. The qPCR method was performed for 22q11.2 microdeletions detection as a first-level screening approach in a genetically unknown series of patients with congenital heart defects. A technical issue related to the VPREB1 qPCR marker was pointed out.MethodsA set of 100 unrelated Italian patients with congenital heart defects were tested for 22q11.2 microdeletions by a qPCR method using six different markers. Fluorescence In Situ Hybridization technique (FISH) was used for confirmation.ResultsqPCR identified six patients harbouring the 22q11.2 microdeletion, confirmed by FISH. The VPREB1 gene marker presented with a pattern consistent with hemideletion in one 3 Mb deleted patient, suggestive for a long distal deletion, and in additional five non-deleted patients. The long distal 22q11.2 deletion was not confirmed by Comparative Genomic Hybridization. Indeed, the VPREB1 gene marker generated false positive results in association with the rs1320 G/A SNP, a polymorphism localized within the VPREB1 marker reverse primer sequence. Patients heterozygous for rs1320 SNP, showed a qPCR profile consistent with the presence of a hemideletion.ConclusionsThough the qPCR technique showed advantages as a screening approach in terms of cost and time, the VPREB1 marker case revealed that single nucleotide polymorphisms can interfere with qPCR data generating erroneous allelic copy number interpretations.

Multiple Cerebral Hemorrhagic Foci From Metastases During Temozolomide Treatment in a Patient With Corticotroph Pituitary Carcinoma

Pituitary carcinoma is a rare disorder accounting for 0.1–0.5% of pituitary neoplasia (1, 2), with a poor prognosis despite maximal multimodal standard therapies. Temozolomide has been suggested as effective in treating pituitary carcinomas (3–5). Here, we describe the case of a 58-year-old man with active Cushing’s disease due to a huge pituitary tumor. Repeated adenomectomy failed to control the disease. Histology examination revealed a pituitary adenoma, with positive immunostaining for ACTH and a Ki-67 proliferation index of 10%, whereas Crooke’s cells were absent. Ketoconazole and cabergoline treatment being ineffective, conventional radiotherapy (48.6 Gy) was administered. Five years later, magnetic resonance imaging showed a residual pituitary lesion of 28 16 mm with suprasellar extension. The hormonal evaluation indicated persistent severe hypercortisolism. Bilateral adrenalectomy was then performed. Twelve months later, plasma ACTH levels dramatically increased (up to 1250 pg/mL), and the pituitary neoplasm extended to the clivus and the C2 body (Figure 1A). Liver, vertebral, and meningeal lesions were detected (Figure 1B); biopsies of hepatic lesions confirmed ACTH-positive neuroendocrine metastases. Temozolomide (160 mg/m daily for 5 d) was started. Plasma ACTH levels were unaffected; 27 days later, the patient complained of severe headache, blindness, and rigor nucalis. He was admitted to the intensive care unit where severe thrombocytopenia (18 000/mm), a previously reported adverse event of temozolomide (3), and multiple cerebral hemorrhagic foci from metastases were diagnosed (Figure 1, C and D). He died a few months after discharge. This case report emphasizes the risk of hemorrhages associated with temozolomide and the need for careful management in patients with aggressive pituitary tumors.

Asymptomatic myotonia congenita unmasked by severe hypothyroidism

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients.