Judit Toke

Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study

OBJECTIVE Despite the increased prevalences of hypertension, type 2 diabetes mellitus (T2DM), hyperlipidemy, and obesity in patients with non-functioning adrenal adenomas (NFAAs), there is a paucity of data on long-term atherosclerotic morbidity as well as the long-term cardiovascular effects of adrenalectomy in these patients. DESIGN, PATIENTS, AND METHODS This retrospective study includes the results of baseline and follow-up investigations of 125 patients (29 males and 96 females; mean age 60.1 years) with NFAAs referred for endocrine evaluation between 1990 and 2001. Of the 125 patients, 47 underwent unilateral adrenalectomy, while 78 patients were followed conservatively. These patients were reinvestigated after a mean follow-up time of 9.1 (5-16) years in 2006, with special emphasis on laboratory and other atherosclerotic risk factors (ARF), vascular events, and interventions. RESULTS The prevalences of hypertension, impaired glucose tolerance or T2DM, hyperlipidemy, and obesity were 82, 43, 58, and 50%, and 89, 58, 82, and 50% at baseline and follow-up, respectively. None of the investigated ARF prevalences were different between patients treated and not treated with adrenalectomy, and between patients with and without subclinical Cushings syndrome. The prevalences of angina pectoris, acute myocardial infarction, coronary, and peripheral arterial interventions or cerebrovascular stroke did not differ significantly between patients treated and not treated with adrenalectomy. CONCLUSION Our study confirms previous investigations reporting markedly increased prevalences of various ARF in patients with NFAAs. Adrenalectomy performed in these patients failed to decrease the prevalence of ARF and atherosclerotic morbidity.

Ghrelin: A new peptide regulating the neurohormonal system, energy homeostasis and glucose metabolism

Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders. Copyright

Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing's syndrome

SummaryWe examined bone densitometric data in a four-year follow-up period before and after the cure of CS. Plasma cortisol concentrations were similar, but the duration of estimated glucocorticoid excess was longer in patients with prevalent bone fractures compared to those without fractures. After therapy of CS, bone area, BMC and BMD increased significantly at the LS and femur during follow-up, but they decreased at the forearm, suggesting redistribution of bone minerals from the peripheral to the axial skeleton.IntroductionOnly a few studies report the changes in bone mineral density (BMD) after the cure of Cushing’s syndrome (CS).MethodsForty-one patients with Cushing’s disease, 21 patients with adrenal CS and 6 patients with ectopic CS were prospectively enrolled. BMD, bone mineral content (BMC) and bone area were measured by DXA.ResultsNo significant correlations were found between serum cortisol concentrations and baseline bone densitometric data. After successful therapy of CS, bone area and BMD increased significantly at the lumbar spine (LS) and femur during follow-up, but they decreased at the forearm. The progressive increase in BMC at the LS had a significant negative correlation with the change of the BMC of radius in the first and second follow-up years. The change in the body mass index was an independent predictor for changes in BMC both at the LS and at the forearm at the second year of remission.ConclusionsThe regional differences and the time-dependent changes of BMC suggest that the source of marked increase in axial BMC after the cure of CS is, at least partly, due to the redistribution of bone minerals from the peripheral to the axial skeleton.

BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism.

Objective  The hypothalamic–pituitary–adrenal axis setpoint and the glucocorticoid sensitivity of various tissues are at least partially genetically determined. We investigated the impact of glucocorticoid receptor (GR) gene polymorphisms, including the BclI, N363S, ER22/23EK and A3669G variants on bone turnover and/or mineral density (BMD) in patients with endogenous glucocorticoid excess.

Methods for the analysis of large gene deletions and their application in some hereditary diseases

Complete or partial gene deletions and copy number variations of disease-causing genes have pathophysiological significance in several monogenic hereditary diseases. Direct DNA sequencing is not suitable for the detection of these genetic abnormalities. In this work, authors review methods of large gene deletion testing and present their own results in two monogenic diseases to demonstrate the application of current methods in clinical practice. Classical methods (chromosome banding, Southern-hybridisation, fluorescent in situ hybridisation), polymerase chain reaction-based techniques (denaturing high performance liquid chromatography, quantitative real-time polymerase chain reaction, microsatellite marker analysis, multiple amplifiable probe hybridisation, multiple ligation probe amplification) as well as techniques based on recent advances in bioinformatics (comparative genome hybridisation, array-based analysis) are presented. Finally, authors present their own findings on large deletion testing of the VHL gene using quantitative real-time polymerase chain reaction and multiple ligation probe amplification in patients with von Hippel-Lindau disease and review a simple polymerase chain reaction method for the detection of large deletion of the CYP21A2 gene in patients with congenital adrenal hyperplasia.

Plasma ghrelin response to an oral glucose load in growth hormone-deficient adults treated with growth hormone

ZusammenfassungHINTERGRUND: Die Pathophysiologie der Ghrelin-Sekretion bei Wachstumshormon-defizienten Erwachsenen unter Therapie mit Wachstumshormon ist weitgehend unbekannt. Auch die Beziehung zwischen Plasma-Ghrelin-Spiegeln und einer durch eine orale Glukosebelastung induzierten Hyperinsulinämie wurde in solchen Patienten noch nicht erforscht. ZIEL DER STUDIE: In der vorliegenden Studie untersuchten wir die Beziehung zwischen Plasma-Ghrelin, Insulin, C-Peptid und Leptin nach einer oralen Glukosebelastung bei Wachstumshormon-defizienten Erwachsenen, die unter einer Therapie mit Wachstumshormon standen. METHODEN: Plasma-Ghrelin, Leptin, Insulin, C-Peptid und Blutzucker wurden vor sowie 30, 60, 90 und 120 Minuten nach der oralen Einnahme von 75 g Glukose bei 20 Wachstumshormon-defizienten Erwachsenen (12 Frauen, 8 Männer), die 7,2 ± 1,3 (MW ± SE) Jahre mit Wachstumshormon behandelt worden waren, gemessen. Plasma-Ghrelin wurde vor und nach einer Glukosebelastung bei 10 gesunden im Alter und Gewicht entsprechenden Personen (5 Männer, 5 Frauen) gemessen. ERGEBNISSE: Die orale Glukosebelastung bewirkte bei Wachstumshormon-defizienten Patienten und bei Gesunden eine prozentuell ähnliche Unterdrückung des Plasma-Ghrelins. In beiden Gruppen sank das Plasma-Ghrelin 30 Minuten nach der Glukosegabe signifikant und blieb von da ab bis zum Ende der Untersuchung unterdrückt. Bei den Wachstumshormon-defizienten Patienten zeigten Insulin (basal 15,9 ± 3,9 µIU/ml) und C-Peptid (basal (2,5 ± 0,3 ng/ml) gegenläufige Veränderungen mit Spitzenwerten 30 Minuten (Insulin: 109,5 ± 15,6 µIU/ml) bzw. 60 Minuten (C-Peptid: 10,3 ± 1,1 ng/ml) nach der Glukosegabe. Zum Unterschied vom basalen Ghrelin korrelierte bei diesen Patienten das post-Glukose Plasma-Ghrelin negativ mit dem Plasma-Insulin, dem C-Peptid und den Blutzuckerwerten. Das basale Ghrelin korrelierte invers mit dem basalen Plasma-Leptin. SCHLUSSFOLGERUNGEN: Die Unterdrückung von Plasma-Ghrelin nach einer oralen Glukosebelastung bei Wachstumshormon-defizienten Patienten unter Wachstumshormon-Therapie ist ähnlich der bei Gesunden beobachteten; dies spricht gegen eine gestörte Regulation der Ghrelin-Sekretion bei diesen Patienten. Die Korrelationen zwischen post-Glukose Plasma-Ghrelin, Insulin und Blutzucker machen einen schon früher vorgeschlagenen Zusammenhang zwischen einer Hyperinsulinämie (bzw. einem erhöhten Blutzucker) und der Suppression der Ghrelin Spiegel wahrscheinlich.SummaryBACKGROUND: Little is known about the pathophysiology of ghrelin secretion in growth hormone-deficient adults treated with growth hormone, and the relationship between plasma ghrelin and hyperinsulinemia induced by an oral glucose load has not been investigated in these patients. OBJECTIVE: In the present study we examined the relationship between plasma ghrelin, insulin, C-peptide and leptin after an oral glucose load in growth hormone-deficient adults receiving treatment with growth hormone. METHODS: Plasma ghrelin, leptin, insulin, C-peptide and blood glucose were measured before and then at 30, 60, 90 and 120 min after the ingestion of glucose (75 g orally) in 20 growth hormone-deficient adults (12 women and 8 men), who had been treated with growth hormone for 7.2 ± 1.3 years (mean ± SE). Plasma ghrelin was also determined before and after the glucose load in 10 age-and weight-matched healthy persons (5 women and 5 men). RESULTS: The oral glucose load induced a similar percent suppression of plasma ghrelin in the growth hormone-deficient patients and in the healthy persons. In both groups plasma ghrelin decreased significantly 30 min after the glucose load and remained suppressed throughout the test period. In the patients plasma insulin (baseline, 15.9 ± 3.9 µIU/ml) and C-peptide (baseline, 2.5 ± 0.3 ng/ml) showed opposite changes with peak responses at 30 min (insulin, 109.5 ± 15.6 µIU/ml) or 60 min (C-peptide, 10.3 ± 1.1 ng/ml). In these patients, post-glucose, but not baseline plasma ghrelin levels correlated negatively with plasma insulin, C-peptide and blood glucose levels, whereas baseline plasma ghrelin correlated inversely with baseline plasma leptin. CONCLUSIONS: The similar suppression of plasma ghrelin in growth hormone-deficient patients treated with growth hormone and in healthy persons after an oral glucose load argues against disturbed regulation of ghrelin secretion in these patients. The correlations between post-glucose plasma ghrelin, insulin and blood glucose support the existence of a previously proposed link between hyperinsulinemia (or increased blood glucose) and suppression of ghrelin levels.

A laboratóriumi diagnosztika eredményei az elmúlt 20 évben kórismézett 155 phaeochromocytoma/paraganglioma szindrómás beteg adatainak elemzése alapján

Bevezetés: A phaeochromocytoma-paraganglioma szindróma laboratóriumi kórismézése jelentős fejlődésen ment keresztül az utóbbi két évtizedben. Célkitűzés: Jelen vizsgálat célja, hogy retrospektív elemzéssel bemutassa és értékelje a Semmelweis Egyetem, II. Belgyógyászati Klinikán 1993–2013 között diagnosztizált phaeochromocytomás/paragangliomás betegek klinikai és laboratóriumi adatait. Módszer: A vizeletkatecholaminokat és metabolitjaikat nagy felbontású folyadékkromatográfiát követő elektrokémiai detektálással mérték 155 phaeochromocytoma-paraganglioma szindrómás (28,4%-uk örökletes hátterű) betegben és 170 nem phaeochromocytomás egyénben. A szérum-chromogranin-A-t immunradiometriás módszerrel vizsgálták. Eredmények: A 24 órás gyűjtött vizeletben a frakcionált metanephrinek szenzitivitása (93,2%) és specificitása (87,0%) meghaladta a katecholaminok (90,9% és 85,7%) és a szérum-chromogranin-A-meghatározás (88,7%, illetve 77,5%) hasonló értékeit. A vizeletnormetanephrin, illetve a szérum-chromogranin-A pozitív összefüggést mutatott a daganatátmérővel (r = 0,552, p<0,0001, illetve r = 0,618, p<0,0001). Következtetések: Az eredmények a vizelettel ürülő katecholaminmetabolitok meghatározásának jelentőségét igazolják a phaeochromocytoma-paraganglioma diagnosztikájában. A vizeletnormetanephrin és a szérum-chromogranin-A segíthet a tumortömeg és a progresszió megítélésében. Orv. Hetil., 2015, 156(16), 626–635.INTRODUCTION Laboratory diagnosis of pheochromocytoma-paraganglioma syndrome has been markedly improved during the past two decades. AIM Retrospective assessment of diagnostic utility of urinary catecholamines and their metabolites as well as serum chromogranin A in 155 patients diagnosed at the 2nd Department of Medicine, Semmelweis University. METHOD Urinary catecholamines and metabolites were measured using high-performance liquid chromatography with electrochemical detection in 155 patients with pheochromocytoma-paraganglioma (of whom 28.4% had hereditary background) and in 170 non-pheochromocytoma patients used as controls. Serum chromogranin A was measured by immunoradiometry. RESULTS Sensitivity (93.2%) and specificity (87.0%) of urinary fractionated metanephrines were higher than those of urinary catecholamines (90.9% vs. 85.7%, respectively) and serum chromogranin A (88.7% and 77.5%, respectively). Urinary normetanephrine and serum chromogranin A correlated positively with tumor size (r = 0.552, p<0.0001 and r = 0.618, p<0.0001, respectively). CONCLUSIONS These data confirm the diagnostic utility of urinary catecholamines and their metabolites. Urinary normetanephrine and serum chromogranin A may help to estimate tumour mass and probably tumour progression.

Az ösztradiol hatásai és jelentosége férfiakban

The most important estrogen is estradiol in both men and women. In men elevated estradiol levels and associated metabolic disorders have been implicated in the development of common diseases including cardiovascular disorders, insulin resistance and type 2 diabetes mellitus, as increased estradiol associated with decreased testosterone levels increases the risk of these diseases. In this review the authors summarize the causes and consequences of androgen deficiency and estradiol excess, and they review recent studies on potential therapeutic strategies to correct increased estradiol levels in men.

Extracellular calcium sensing under normal and pathological conditions

Ionic calcium has been known as an important intracellular second messenger for many decades. In addition, a whole series of experimental and clinical studies from the past fifteen years have provided evidence that extracellular ionic calcium itself is also a first messenger, since it is the ligand of a cell surface G-protein coupled receptor called calcium-sensing receptor. This review summarizes the current knowledge on the role of calcium-sensing receptor in the maintenance of calcium homeostasis, its functions in various tissues and some of the most important disorders characterized by defective calcium sensing. The inherited disorders of the calcium-sensing receptors may be classified as the results of loss-of-function and gain-of-function mutations of the calcium-sensing receptor gene. Loss-of-function heterozygous mutations lead to familial hypocalciuric hypercalcemia while homozygous mutations result in the frequently life-threatening disorder called neonatal severe hyperparathyroidism. Gain-of-function mutations of this receptors gene cause the disorder called autosomal dominant hypocalcemia. The authors briefly highlight the clinical features, laboratory characteristics and therapeutic implications of these disorders. Also, they discuss briefly the molecular mechanisms resulting defective calcium-sensing in of patients with primary and secondary hyperparathyroidism, and summarize the results of some recent investigations on the functional consequences of genetic variants of the calcium-sensing receptor gene.