Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow-up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed.
M Peracchi, D Conte, C Gebbia, C Penati, S Pizzinelli, M Arosio, S Corbetta and A Spada
OBJECTIVE: As circulating chromogranin A (CgA) has been claimed to be the best general neuroendocrine marker so far available, we evaluated the usefulness of CgA determination in the clinical assessment of patients with sporadic gastro-entero-pancreatic neuroendocrine tumors (GEP NETs) or multiple endocrine neoplasia type 1 (MEN 1). DESIGN AND METHODS: Plasma CgA levels were measured using a commercial enzyme-linked immunosorbent assay in 61 patients with sporadic GEP NET and in 25 with MEN 1 including 16 with GEP NET. Controls were 50 healthy volunteers, 46 patients with pituitary adenoma and 35 patients with primary hyperparathyroidism. RESULTS: The cutoff value for CgA established in our healthy subjects (as mean+2 s.d.) was 20 U/l. CgA levels were above the normal range in 71/77 patients with sporadic or MEN 1-related GEP NETs (92%), in four out of nine MEN 1 patients without GEP NETs (44%), and only in 22/81 control patients with pituitary or parathyroid disease (27%). Furthermore, CgA levels of over 100 U/l occurred in 36/77 patients with GEP NETs (47%) and only in one patient with a non-functioning pituitary adenoma. In the patients with GEP NETs, both tumor burden and secretory activity affected CgA levels, and successful surgical resection was associated with markedly decreased CgA values. CONCLUSIONS: Plasma CgA was confirmed to be a reliable marker for GEP NETs. Moreover, in MEN 1 patients the finding of very high CgA levels strongly suggests the presence of a GEP NET, as both primary hyperparathyroidism and pituitary adenomas rarely cause marked CgA increases.
S Corbetta, P Englaro, S Giambona, L Persani, WF Blum and P Beck-Peccoz
Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.
S Corbetta, R Angioni, A Cattaneo, P Beck-Peccoz and A Spada
Objective: In vitro and in vivo models indicate that all-trans retinoic acids influence glucose and lipid metabolism. We aimed to evaluate the effects of chronic treatment with acitretin, an all-trans retinoic acid, on glucose metabolism, lipid profile and adiponectin and resistin levels.
Design: Ten normoglycemic, normolipemic patients affected with psoriasis vulgaris were studied before and after 1 and 3 months of oral treatment with 35 μg of acitretin.
Methods: Glucose metabolism, lipid profile, and adiponectin and resistin levels were evaluated in basal conditions and after acitretin treatment. Ten healthy subjects matched for age, body mass index (BMI) and insulin sensitivity were studied as controls.
Results: One-month acitretin treatment reduced psoriasis activity, insulin sensitivity, evaluated as QUICKI values (0.364 ± 0.034 versus 0.329 ± 0.051; P < 0.05) and HOMA-IR index (1.53 ± 0.73 versus 2.59 ± 1.41; P < 0.05), and high-density lipoprotein (HDL)-cholesterol levels (45.2 ± 11.7 versus 39.4 ± 10.4 mg/dl; P = 0.01). The impairment in glucose and lipid homeostasis was transient and not associated to BMI variations. Adiponectin levels did not change during the treatment, while resistin levels, which were higher in untreated patients than in controls (9.4 ± 4.4 versus 6.2 ± 2.1 ng/ml; P = 0.05), fell within the normal range after 1 and 3 months of therapy. The normalization of resistin levels occurred without significant changes in circulating tumor necrosis factor α (TNFα) levels, which persisted elevated throughout the treatment.
Conclusions: Treatment with a low dose of acitretin induced a mild, transient reduction of insulin sensitivity and HDL-cholesterol levels that was not related to modifications of adiponectin, resistin and TNFα levels. Although the role of resistin in humans remains elusive, the levels of this adipocytokine seem to be affected, at least in part, by retinoids.
A Lania, E Ballare, S Corbetta, M Filopanti, L Persani and A Spada
OBJECTIVE: The GH-releasing peptide GHRP-6, has been found to interact with specific receptors in somatotrophs, causing cytosolic Ca2+ ([Ca2+]i) rise and GH release. Moreover, this peptide has been demonstrated to stimulate the secretion of pituitary hormones other than GH, i.e. ACTH and prolactin, this effect being generally attributed to a central action. In this study we evaluated whether the pituitary action of this peptide is restricted to cell type of somatotroph lineage. METHODS: The effect opf GHRP-6 on [Ca2+]i was tested in cell preparations obtained from a series of human pituitary adenomas (9 GH-secreting adenomas, 7 nonfunctioning adenomas, 3 ACTH-secreting adenomas, 2 TSH-secreting adenomas and 1 prolactinoma) loaded with the Ca2+ indicator fura-2. RESULTS: GHRP-6, at concentrations higher than 1 nmol/l, significantly increased [Ca2+]i in all tumours, with the exception of the 3 ACTH-secreting adenomas in which the peptide was ineffective at any concentration tested (from 1 nmol/l to 1 micromol/l). By contrast, in all ACTH-secreting adenomas, both corticotrophin-releasing hormone and pituitary adenylate cyclase activating peptide caused a marked [Ca2+]i increase. In tumours responsive to GHRP-6, the peptide caused a typical biphasic [Ca2+]i rise due to Ca2+ mobilization from the intracellular stores and Ca2+ influx through voltage-dependent Ca2+ channels. CONCLUSIONS: These data indicate that almost all tumoral pituitary cell types are targets of GHRP-6 action, the only exception being corticotrophs.
S Corbetta, C Eller-Vainicher, M Frigerio, R Valaperta, E Costa, L Vicentini, A Baccarelli, P Beck-Peccoz and A Spada
Primary hyperparathyroidism (PHPT) is often complicated by kidney stones. Hypercalciuria and urine oxalate excretion are considered risk factors for urolithiasis in PHPT as well as in idiopathic stone-formers. Recently, the anion-exchanger SLC26A6 has been involved in the oxalate metabolism.
Design and methods
We tested the hypothesis that the 206M polymorphic variant of SLC26A6 gene might contribute to the risk of kidney stones in PHPT. DNA samples from 145 PHPT patients and 129 age- and sex-matched healthy subjects were genotyped.
The homozygous 206V genotype was the most frequent both in PHPT patients and controls (79.3 and 74.4%), while heterozygosity for the 206M allele was detected in 20.0 and 23.3% respectively. The homozygous 206M genotype was extremely rare, occurring in 0.7 and 2.3% of PHPT and healthy subjects respectively. In the PHPT cohort, the prevalence of urolithiasis did not differ between the V/V and V/M+M/M groups and urine oxalate excretions did not correlate with the genotype. Considering the subset of PHPT stone formers (n=74), calciuria was lower in V/M+M/M patients with respect to V/V stone-formers (4.40±1.88 vs 5.92±2.62 mg/kg per 24 h; mean±s.d., P=0.034). Finally, the SLC26A6 206M alleles were significantly related to the presence of hypertension (73.3 vs 47.8%), showing an OR of 4.8.
Though the SLC26A6 206M polymorphism did not correlate with kidney stone development in PHPT patients, PHPT stone-formers harbouring the M allele had a lower hypercalciuria. This observation and the high prevalence of hypertension associated with the 206M polymorphism need further investigation.
CL Ronchi, S Corbetta, V Cappiello, PS Morpurgo, C Giavoli, P Beck-Peccoz, M Arosio and A Spada
OBJECTIVE: Adiponectin (ApN) is an adipocytokine expressed in human adipose cells with anti-atherogenic and anti-inflammatory properties that plays a role in the pathophysiology of insulin resistance, metabolic syndrome and coronary artery disease. The aim of the study was to evaluate ApN secretion in patients with acromegaly, a chronic disease associated with insulin resistance and increased cardiovascular mortality, and to correlate ApN levels with hormonal, metabolic and cardiovascular parameters. DESIGN AND METHODS: The study included 32 patients with active acromegaly (11 male and 21 female, aged 48+/-11 years, duration of disease: 8+/-6 years, GH: 9.2+/-9.8 microg/l, IGF-I: 80+/-33 nmol/l (means+/-s.d.)) and 38 control subjects sex- and body mass index (BMI)-matched. In all subjects, serum ApN, leptin and ghrelin levels, BMI, waist circumference, insulin resistance (assessed by homeostasis model assessment and the quantitative insulin check index), lipid profile and blood pressure values were evaluated. RESULTS: Acromegalic patients and control subjects had similar ApN levels (9.4+/-3.5 vs 9.5+/-4.0 mg/l, NS), while when considering obese subjects acromegalic patients had ApN levels significantly higher than controls (10.2+/-4 vs 7.5+/-3 mg/l, P<0.05). No significant correlation between ApN and GH/IGF-I levels or duration of disease was found. ApN concentrations negatively correlated with BMI, waist circumference, glucose and diastolic blood pressure and positively with high-density lipoprotein cholesterol and ghrelin in controls, while all these correlations were lost in acromegalic patients. CONCLUSIONS: We provide evidence that, although metabolic and cardiovascular abnormalities are present in most acromegalic patients, in these subjects ApN levels are not reduced and, contrary to what is found in BMI-matched controls, do not correlate with cardiovascular risk factors. These data support the view that atherosclerosis is not the main determinant of cardiovascular mortality in acromegaly and suggest a permissive action of GH and/or IGF-I excess on ApN secretion.
C L Ronchi, C Giavoli, E Ferrante, E Verrua, S Bergamaschi, D I Ferrari, S Corbetta, L Montefusco, M Arosio, B Ambrosi, A Spada and P Beck-Peccoz
Radiotherapy (RT) for pituitary adenomas, including GH-secreting ones, frequently leads to GH deficiency (GHD). Data on the effects of surgery alone (S) on dynamic GH secretion are limited. The aim of the study was to investigate the occurrence of GHD in acromegalic patients treated with different therapeutic options.
Design and methods
Fifty-six patients in remission from acromegaly, (33 F & 23 M, age: 54±13 years, body mass index (BMI): 28.4±4.1 kg/m2, 21 with adequately substituted pituitary deficiencies) treated by S alone (n=33, group 1) or followed by RT (n=23, group 2), were investigated for GHD by GHRH plus arginine testing, using BMI-adjusted cut-offs. Several metabolic and cardiovascular parameters (waist circumference, body fat percentage, blood pressure, fasting and post-oral glucose tolerance test glucose, HbA1c, insulin resistance and lipid profile) were evaluated in all the patients and 28 control subjects with known diagnosis of GHD.
Serum GH peak after challenge was 8.0±9.7 μg/l, without any correlation with post-glucose GH nadir and IGF-1 levels. The GH response indicated severe GHD in 34 patients (61%) and partial GHD in 15 patients (27%). IGF-1 were below the normal range in 14 patients (25%). The frequency of GHD was similar in the two treatment groups (54% in group 1 and 70% in group 2). No significant differences in metabolic parameters were observed between acromegalic patients and controls with GHD.
Severe GHD may occur in about 60% of patients treated for acromegaly, even when cured after S alone. Thus, a stimulation test (i.e. GHRH plus arginine) is recommended in all cured acromegalic patients, independently from previous treatment.
S Corbetta, C Eller-Vainicher, M Filopanti, P Saeli, G Vezzoli, T Arcidiacono, P Loli, M L Syren, L Soldati, P Beck-Peccoz and A Spada
Context: Primary hyperparathyroidism (PHPT) shows a great variability in clinical course and severity. Data concerning the association between polymorphic variants of the gene encoding the calcium-sensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive.
Objective: To evaluate the frequency of three polymorphisms; A986S, R990G, and Q1011E of CaSR in patients with PHPT and to correlate the genotypes with clinical and biochemical parameters.
Patients and methods: The study included 94 consecutive unrelated patients referred to our Departments for PHPT diagnosis and management between 2000 and 2005 and 137 age and sex-matched healthy subjects. Patients and controls were genotyped according to standard procedures. Due to the rarity of 990G allele, homozygous and heterozygous subjects were grouped in R/G+G/G set. All PHPT patients were studied for calcium metabolism parameters and renal and bone complications.
Results: The proportion of CaSRvariants was similar in PHPT patients and controls. In PHPT patients, only R990G polymorphism was associated with disease parameters; in comparison with R/R, R/G+G/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9 ± 62.2 vs 199.9 ± 136.3 pg/ml, P < 0.05 and 0.69 ± 0.12 vs 0.81 ± 0.18 mmol/l, P = 0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05 ± 2.05 vs 6.77 ± 4.31 mmol/24 h, P = 0.012 and 67 ± 20 vs 51 ± 26 μmol/l GF, P = 0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, P = 0.007).
Conclusions: The study showed that patients with PHPT, bearing the 990G allele, had lower serum PTH levels and higher urinary calcium excretion in comparison with the other genotype, suggesting an increased sensitivityof the variant receptor to extracellular calcium. Since this variant was associated with increased occurrence of nephrolithiasis, analysis of this polymorphism might help to predict renal complication of the disease.
M Filopanti, A M Barbieri, G Mantovani, S Corbetta, V Gasco, M Ragonese, C Martini, F Bogazzi, A Colao, D Ferone, A Peri, F Pigliaru, G Angeletti, M Arosio, P Beck-Peccoz, A G Lania and A Spada
Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome.
To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.
Design and setting
Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.
A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.
Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.
No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found.
UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.