K. Rácz

One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel®

objective  Somatostatin analogue treatment is first‐line medical therapy for acromegaly. This study compared the efficacy and tolerability of titrated doses of the long‐acting somatostatin analogue preparation lanreotide Autogel® with fixed doses and with lanreotide prolonged release (PR) 30 mg microparticles.

Clinical and biochemical features of sporadic and hereditary phaeochromocytomas: an analysis of 41 cases investigated in a single endocrine centre

The aims of this study were to estimate the prevalence of phaeochromocytomas among adrenal tumours and to analyse the clinical and biochemical features of sporadic and hereditary tumours. Our series of 609 adrenal tumours evaluated between January 1995 and July 2003 was reviewed. Catecholamine content in phaeochromocytoma tissues was also determined and correlated with clinical behaviour and biochemical parameters of patients. Forty-one (6.7%) of the 609 patients had phaeochromocytomas, of which 28 were sporadic (25 benign and three malignant) and 13 (all benign) were associated with hereditary diseases (multiple endocrine neoplasia type 2A in seven cases from four unrelated families carrying mutations of the RET gene, von Hippel–Lindau disease in two unrelated cases with mutations of the VHL gene, and type 1 neurofibromatosis in four unrelated cases). Bilateral tumours were found in three patients with hereditary syndromes and in one sporadic case. Tumour diameter was slightly but not significantly greater in patients with hereditary than in those with sporadic tumours. Systolic but not diastolic blood pressure was significantly higher in patients with sporadic compared with those with hereditary tumours, but comparison of other clinical data and biochemical parameters indicated an absence of significant differences in the mean age, presenting symptoms, heart rate, or fasting serum glucose levels. Tissue catecholamine content measured in 8 sporadic and 5 hereditary phaeochromocytomas was highly variable and it failed to show significant differences between hereditary and sporadic tumours. These results indicate a high proportion of hereditary diseases among patients with phaeochromocytomas. Genetic and clinical testing for hereditary diseases may be of great help to offer an appropriate treatment, follow-up and family screening for these patients.

Granulomatous hypophysitis associated with Takayasu's disease

We report a case of Takayasus disease, presenting with symptoms of fever, anaemia, elevated erythrocyte sedimentation rate, anterior pituitary failure and mild diabetes insipidus. A pituitary mass with suprasellar extension mimicking a pituitary adenoma was found, and histological examination revealed granulomatous hypophysitis. The diagnosis of Takayasus disease was established after the development of a multiple arterial occlusive disease. We suggest that Takayasus disease should be considered in the differential diagnosis of granulomatous hypophysitis of unknown origin.

Ovarian steroid cell tumor and a contralateral ovarian thecoma in a postmenopausal woman with severe hyperandrogenism

A 49-year-old woman presented with rapidly progressing hirsutism, receding hairline, male-pattern baldness and deepening of voice, which had developed over the past 2 years. Hormonal evaluation showed a markedly elevated serum testosterone level (418 ng/dl) and no evidence of increased production of cortisol, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, or 17-hydroxyprogesterone. Transvaginal ultrasound examination suggested the presence of a small mass within the left ovary, but all other radiological studies, including adrenal and ovarian computed tomography, magnetic resonance imaging, radio-labelled cholesterol scintigraphy and positron emission tomography, were negative. Subsequently, bilateral selective venous sampling showed a marked testosterone gradient in the right ovarian vein. Bilateral salpingo-oophorectomy was performed (the patient had had a previous vaginal hysterectomy), and histopathological examination revealed a 10-mm steroid cell tumor within the right ovary and a 15-mm thecal cell tumor within the left ovary. The postoperative serum testosterone level returned to normal and the patient showed a slow regression of clinical symptoms. The simultaneous occurrence of a virilizing ovarian steroid cell tumor and an apparently non-functioning thecoma within the contralateral ovary emphasizes the potential pitfalls that may exist in the preoperative evaluation of patients with markedly increased testosterone production.

Effects of 24 Months of Growth Hormone (GH) Treatment on Serum Carboxylated and Undercarboxylated Osteocalcin Levels in GH-Deficient Adults

We studied the effect of growth hormone (GH) replacement on bone mineral density (BMD) and some parameters of bone metabolism, including undercarboxylated osteocalcin (ucOC), an independent predictive marker of fracture risk, which has not been previously determined or compared during GH treatment. Measurements were performed at baseline and after 6, 12, 18 and 24 months of the initiation of the GH therapy in 21 adult patients with GH deficiency. Significant increases were observed in BMD after 1 year at the lumbar spine and after 1.5 years at the femoral neck. Serum total OC and carboxylated (c) OC increased and reached the maximum at 6 months, but the values remained over the baseline at both 12 and 18 months. The ucOC:total OC ratio changed contrarily: it decreased at 6 months, then increased again and reached the baseline level during the next 18 months. Serum calcium (Ca), phosphate (P) and total alkaline phosphatase (ALP) levels increased after 6 months, thereafter the Ca and P values decreased, while the total ALP remained elevated until 12 months. Serum parathormone decreased at 12 months and increased again thereafter. GH replacement therapy is associated with improvement of ucOC, a marker of fracture risk, which in addition to the increase of BMD, might contribute to the beneficial effect of GH replacement therapy on bone metabolism.

Acth sensitivity of isolated human pathological adrenocortical cells: Variability of responses in aldosterone, corticosterone, deoxycorticosterone and cortisol production

In vitro aldosterone, deoxycorticosterone, corticosterone and cortisol production of human adrenocortical cells derived from adenomas (Conns syndrome, Cushings syndrome), from hyperplastic adrenals (Cushings syndrome) and from adrenals surrounding aldosteronoma are described. Cells from adenomas causing either Cushings syndrome or Conns syndrome harboured the highest basal and ACTH-stimulated corticosteroid production. Adrenocortical cells derived from micronodular hyperplasia causing Cushings syndrome and cells from cortisol producing adenoma displayed predominantly cortisol and corticosterone secretion both under basal conditions and following stimulation with ACTH. Aldosteronoma cells showed highly variable aldosterone, deoxycorticosterone, corticosterone and cortisol response to ACTH. However, in aldosteronoma cell suspensions, the basal and ACTH-stimulated ratios of aldosterone to cortisol were increased when compared to ratios of steroids produced by cells from other adrenal tissues. Chronic treatment with spironolactone of patients with Conns syndrome before surgery was associated with a decreased ratio of aldosterone to corticosterone, revealing that 18-hydroxylase in aldosteronoma cells may be inhibited during long-term therapy. Non-tumorous cells isolated from adrenals surrounding aldosteronoma displayed less aldosterone prior to and after stimulation with ACTH than aldosteronoma cells.

Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies ☆

BACKGROUND The secondary forms of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (secondary TMA) emerge as complications of coexisting diseases. OBJECTIVES We hypothesized that secondary TMA could be characterized by the presence of relative ADAMTS13 deficiency and complement activation, and this relationship may have a prognostic value for outcome. PATIENTS AND METHODS Fifty-three patients with thrombotic microangiopathy (TMA) and coexisting disease (such as malignancies, sepsis, heart surgery with extracorporeal circulation, solid organ transplantation, systemic autoimmune disorders), 41 patient controls, and 34 healthy controls were enrolled in our case-control study with 30days follow-up. Complement profile (from serum) and activation products, von Willebrand factor (VWF, from EDTA plasma), and ADAMTS13 activity were determined. RESULTS ADAMTS13 activity was reduced, while VWF level was elevated in secondary TMA patients. The activity of the classical, lectin and alternative pathways, as well as the levels of C3, C4, and Factor H were significantly lower in secondary TMA patients, and were accompanied by high activation product levels (C3a and sC5b-9). Factor H concentration correlated to relative ADAMTS13 deficiency (i.e. VWF/ADAMTS13 ratio (r=-0.368, p=0.019)). 28/53 patients (53%) died during the follow-up period. Increased sC5b-9, C3a, and C reactive protein levels were all associated with a poor patient outcome. CONCLUSIONS Our results indicate that the secondary TMA syndrome and its poor outcome is characterized by relative ADAMTS13 deficiency, inflammation, and complement activation with consumption via the classical and alternative pathways. It is yet to be determined whether complement inhibition could be a possible therapeutic option for patients with secondary TMA.

Circulating miRNAs as biomarkers for endocrine disorders

Specific, sensitive and non-invasive biomarkers are always needed in endocrine disorders. miRNAs are short, non-coding RNA molecules with well-known role in gene expression regulation. They are frequently dysregulated in metabolic and endocrine diseases. Recently it has been shown that they are secreted into biofluids by nearly all kind of cell types. As they can be taken up by other cells they may have a role in a new kind of paracrine, cell-to-cell communication. Circulating miRNAs are protected by RNA-binding proteins or microvesicles hence they can be attractive candidates as diagnostic or prognostic biomarkers. In this review, we summarize the characteristics of extracellular miRNA’s and our knowledge about their origin and potential roles in endocrine and metabolic diseases. Discussions about the technical challenges occurring during identification and measurement of extracellular miRNAs and future perspectives about their roles are also highlighted.

Laterality disturbance and hypopituitarism. A case report of co-existing situs inversus totalis and combined pituitary hormone deficiency

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurologicaldefects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe. Despite the presence of situs inversus totalis, thepatient was right-handed and functional MRI demonstrated left-hemisphere activation during language tests. Kartagener syndrome was considered, but immunofluorescence analysis showed normal localization of the outer dynein arm protein in respiratory epithelial cells obtained from the nasal mucosa. Direct DNA sequencing of all coding exons of the pituitary transcription factor 1 (PIT1) and prophet of PIT1 (PROP1) genes failed to detect disease-causing mutations, suggesting that these genes were not involved in the development of CPHD in our patient. More interestingly, the potential role of the paired like homeodomain transcription factor 2 (PITX2) gene, which has been implicated not only in CPHD, but also in left-right patterning in animal models, was also excluded, as sequencing showed the absence of mutations in coding exons of this gene. To our knowledge, PITX2 gene mutations have not been investigated in CPHD patients who had situs inversus totalis. We conclude that in contrast to animal models, the PITX2 gene is not involved in the development of situs inversus totalis, at least not in our CPHD patient.

Effect of single doses of dexamethasone and adrenocorticotrop hormone on serum bone markers in healthy subjects and in patients with adrenal incidentalomas and Cushing’s syndrome

The aim of the present study was to explore whether short-term changes in glucocorticoid activity which occur during dynamic testing of the pituitary adrenal axis with dexamethasone, ACTH, or metyrapone could have an effect on serum osteocalcin (OC) and β-crosslaps (β-CTx) concentrations in healthy subjects, in patients with adrenal incidentalomas and in those with Cushing’s syndrome. The study included 40 healthy subjects (35 women and 5 men, age range 18–69 yr), 49 patients with adrenal incidentalomas (34 women and 15 men, age range 19–77 yr) and 8 patients with Cushing’s syndrome (5 cortisol-producing adenomas and 3 pituitary-dependent Cushing’s syndrome, 3 women and 5 men, age range 19–70 yr). Serum OC and β-CTx concentrations were determined with electrochemoluminescent immunoassays at midnight, after an overnight fast between 08:00 and 09:00 h, after an overnight dexamethasone test (1 mg, orally) and after a single dose of metyrapone (30 mg/kg, orally). In healthy subjects and in patients with adrenal incidentalomas, serum bone marker concentrations were also measured after a single dose of ACTH injection (Cortrosyn depot, 1 mg im). Patients with Cushing’s syndrome, but not those with adrenal incidentalomas, showed significantly lower serum OC at midnight (18.5±12 ng/ml, mean±SD) and between 08:00 and 09:00 h (17.7±9.6 ng/ml) compared to corresponding values obtained in healthy subjects (24.5±7.0 and 28.3±12.2 ng/ml, respectively). Serum OC concentrations were significantly decreased after a single dose of 1-mg dexamethasone in healthy subjects (from 28.3±12.2 to 21.8±9.5 ng/ml) and in patients with adrenal incidentalomas (from 29.8±15.9 to 24.1±14.1 ng/ml), whereas serum OC concentrations remained unchanged in patients with Cushing’s syndrome. In addition, serum OC concentrations were even more markedly decreased after a single dose of ACTH injection in both healthy subjects (12.5±4.6 ng/ml) and in patients with adrenal incidentalomas (12.2±6.5 ng/ml). By contrast, metyrapone administration failed to induce significant changes in OC levels. There were no significant differences in β-CTx concentrations between the three groups or after drug treatments. Thus, serum OC levels should be interpreted with caution when obtained during testing of the pituitaryadrenal axis with dexamethasone or ACTH.