The diagnosis of Cushing's disease (CD) is based on endocrinological parameters. In a certain amount of patients MRI fails to detect a pituitary tumor and extensive pituitary exploration may be necessary. We report on our consecutive series of 50 patients who underwent transsphenoidal surgery under the diagnosis of CD. Out of 50 patients (36 f, 14 m, age 20 – 71 ys, mean FU 40 ms) with typical endocrinological findings for ACTH-dependent hypercortisolism (42 primary cases), in 30 cases microadenomas were suspected or identified by MRI, in 5 cases macroadenomas were visible, and in 15 cases MRI (30%) was negative. IPSS was performed in 13 cases. Microsurgical transsphenoidal surgery was performed using neuronavigation (56 x MRI, 1 x CT) and intraoperative ultrasound (N = 47). Decline of serum-cortisol was monitored to assess early remission.

OBJECTIVE:Localization of microadenomas in Cushing's disease may be difficult as in up to 45% of patients sellar MRI fails to detect a pituitary tumor. Intraoperative transsphenoidal ultrasound may identify microadenomas as hyperechoic structures. We report on the first 18 consecutive cases with intraoperative use of a new device for direct contact high-frequency-ultrasound in patients with Cushing's disease.PATIENTS AND TECHNIQUE:18 patients (14 female, 4 male, age 24-71 years) with typical endocrinological findings for Cushing's disease were included in the study. One macroadenoma and 13 microadenomas were suspected or identified preoperatively by MRI. In 4 cases, two of them with recurrent disease, sellar MRIs were negative. During transsphenoidal microsurgery an end fire ultrasound-probe (B-mode frequency range 7.5-13 Mhz, field of view 5 mm, penetration 20 mm) was introduced after opening of sellar floor. The pituitary gland was scanned in direct contact to the capsule.RESULTS:In 13 out of 17 cases (77%) with later on proven microadenomas high-frequency-ultrasound identified the tumors as hyperechoic masses, including 3 of the 4 cases with negative preoperative MRI. In 2 cases ultrasound correctly localized the tumor at a site different from MRI finding (MRI false positive). In the macroadenoma, identification of the border between tumor and anterior pituitary gland was not possible. In all 18 patients postoperative early decline of serum cortisol to subnormal levels confirmed remission of hypercortisolism (100%). Other pituitary functions were unaltered in 17 cases (94%).CONCLUSIONS:Intraoperative scanning of the pituitary gland with high-frequency-ultrasound probes may identify intrapituitary anatomy and pathologies even in MRI-negative cases. This may prevent extensive exploration of the gland with the risk of subsequent hypopituitarism.

X-Linked hypophosphatemic rickets (HYP, XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. The purpose of our study was the detection of inactivating mutations in the PHEX gene, the key enzyme in the pathogenesis of XLH. The 16 patients, representing eight families, presented with suspected XLH from biochemical and clinical evidence. All 16 were referred for mutational analysis of the PHEX gene. We detected three novel disease-causing mutations, C59S, Q394X, and W602, for which a loss of function can be predicted. A G28S variation, found in two healthy probands, may be a rare polymorphism. Another mutation, A363 V, is localized on the same allele as the C59S mutation, thus its functional consequences cannot be proven. Furthermore, we detected a deletion of three nucleotides in exon 15 which resulted in the loss of amino acid threonine 535. Heterozygosity of this mutation in a male patient without any chromosomal aberrations suggests its presence as a mosaic. Novel large deletions were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. Two of these deletions, loss of exon 22 alone or exons 21 and 22 together, may result in the translation of a C-terminal truncated protein. Two large deletions comprise exons 1-9 and exons 4-20, respectively, and presumably result in a nonfunctional protein. We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA.

Transabdominal sonography of the adrenal glands frequently is non-successful. It was the aim of this project to improve the imaging of the adrenal glands using high resolution sonography in order to obtain information about even small changes in these organs. Therefore, endosonographic imaging was investigated using an endosonoscope PENTAX FG32UA. The correct identification of the adrenal glands was examined in five human cadavers. A total of 58 patients with 113 adrenal glands (in 3 cases history of unilateral adrenalectomy) were investigated. 109 adrenal glands (97%) were identified and evaluated. Healthy adrenal glands are slightly hyperechoich and regarding their echogeneity comparable to other endocrine organs such as the testes or the thyroid. Adrenal size can be determined as largest cross sectional area and was found to be 216 +/- 93 mm2 right and 231 +/- 98 mm2 left. In the adrenal glands which could be imaged by endosonography, all findings detected by CT (n = 33) or MRI (n = 19) could also be demonstrated endosonographically. Additional information as compared to CT/MRI was obtained in 7 out of 33 and in 6 out of 19 patients. This concerns in particular differentiation between tumor and hyperplasia and detection of small adrenal adenomas. High resolution endosonography of the adrenal glands can provide information about adrenal gland morphology which cannot be obtained by any other diagnostic approach.

It is expected that microvascular blood flow might be affected by blood glucose, blood insulin and C-peptide levels. In our investigation skin microvascular blood flow (LDF) was measured using laser doppler fluxometry at skin temperatures of 37 degrees C and 44 degrees C during a 75 g oral glucose load (OGT) or water in ten healthy volunteers (6 male, 4 female, age: 28.1+/-4.0) who had fasted overnight. The transcutaneous oxygen tension (tcPO2) was measured using a transcutaneous oxygen electrode at a temperature of 44 degrees C. The microvascular response to acetylcholine was investigated before the start of the ingestion period and after 30 minutes. In addition, the capillary blood cell velocity (CBV) was measured using dynamic capillaroscopy. During OGT an increase in LDF could be observed at 37 degrees C (180%, p < 0.005) but only a slight increase was observed at 44 degrees C (86%, n.s.). The microvascular response to acetylcholine increased by 164% (p < 0.05) and the TcPO2 values increased by 30% (p < 0.01) during the OGT investigation. No significant changes in the microvascular measurements could be observed during the water experiment. No significant changes could be observed in the CBV measurements in any phase of the investigation. Plasma C-peptide and insulin levels exhibited an association with the LDF measurements at 37 degrees C (r = 0.22, p < 0.05; r = 0.30, p < 0.05; respectively), whereas blood sugar values showed an association with the TcPO2 measurements (r = 0.39, p < 0.01). After the ingestion of glucose a sophisticated modulation of microvascular blood flow was found in healthy volunteers. Further studies are necessary to investigate the role of a disturbed postprandial blood sugar control, insulin and C-peptide secretion in the development of microvascular dysfunction, especially in IDDM.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

BACKGROUND:Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting.OBJECTIVE:To optimize screening and to analyze possible differences in sporadic versus familial cases.METHODS:We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families).RESULTS:A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus.CONCLUSION:In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Background: Somatostatin analogues are the standard medical therapy for acromegaly. There is significant interest in how the use of different treatment regimens (e.g. surgery, medical therapy) impacts the clinical course of disease. This study has been designed to better understand clinical decision making in the context of various treatment options.

Sequential subcutaneous PTH injection therapy (repeated 14 days of PTH administration and a subsequent treatment pause for a few weeks) is known to increase bone mineral density in patients with osteopenic disorders. Alternative methods of drug delivery may be beneficial in increasing compliance. A pilot study was performed in 10 healthy volunteers (4 female/6-male, age: 25.6 +/- 3.5 years, BMI: 22.3 +/- 2.4 kg/m 2, mean +/- SD) to assess the pharmacokinetic profiles of 1600 IU of PTH(1 - 34) using the pulmonary Technosphere drug delivery system in comparison to a subcutaneous injection of 400 IU. The treatments were administered in the morning after an overnight fast and blood samples for measurement of PTH(1 - 34), PTH(1 - 84), and calcium and calcitonin were taken over a period of 6 hours. Both injection and pulmonary application of PTH(1 - 34) were well tolerated. After pulmonary administration of Technosphere/PTH(1 - 34), PTH(1 - 34) appeared in the serum with a faster concentration increase (T max: pulmonary 10 +/- 5 min vs. subcutaneous 28 +/- 8 min, p < 0.001) and with higher maximal concentrations (C max : pulmonary 309 +/- 215 pmol/l vs. subcutaneous 102 +/- 45 pmol/l, p < 0.05) as compared to the subcutaneous injection. The relative bioavailability of pulmonary Technosphere/PTH(1 - 34) was calculated to be 48 %. No differences were seen between pulmonary and subcutaneous application with regard to the PTH(1 - 84), calcitonin and calcium concentrations. In conclusion, pulmonary application of Technosphere/PTH(1 - 34) appears to be an effective and thus attractive candidate for PTH substitution therapy in osteoporosis and other conditions leading to a decrease in bone mineral density.

Topical treatment wit capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatc diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treament (18.3±3.2 vs. 14.3±3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7±0.4°C vs. 11.4±0.7°C; p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9±5.8 pg/ml vs. 81.7±5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4±8.3 pg/ml; n. s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control.

The case of a 25 year old female patient with pseudohypoparathyroidism type I (PHP) and hypercalcitoninaemia is reported. She was referred to our clinic because of recurrent hypocalcaemia associated with paraesthesias and muscle cramps. She had no signs of Albright hereditary osteodystrophy (AHO), a normal mental status and no family history of hypocalcaemia or any other endocrine disease. Considering the laboratory results with hypocalcaemia, hyperphosphataemia, normal vitamin D and normal creatinine with an extraordinary elevated PTH we diagnosed pseudohypoparathyroidism type I. She had delayed pubertal development with menarche in the age of 20 and hypothyroidism with an atrophic thyroid since she was 22 years old. Calcitonin (CT) was increased and the performed pentagastrin test showed an excessive CT-response with a peak of 725 pg/ml after 2 min. Up to now there are only three reports of patients with PHP and hypercalcitoninaemia. An abnormal pentagastrin response is known to be a specific marker for medullary thyroid carcinoma, but there were no signs of any malignant disease, even after one year of follow-up. The most reasonable cause for the pathological pentagastrin response might be chronic hypocalcaemia. When interpreting a pathological pentagastrin test in a patient with PHP the specifity of the test might be diminished and a careful observational strategy might be appropriate.

OBJECTIVE:Endosonography is a powerful tool in the diagnosis of gastroenteropancreatic neuroendocrine tumors. This study was performed in order to characterize endosonographic criteria of malignant and benign neuroendocrine pancreatic tumors focussing on those typically presented to endocrinologists, i.e. insulin-secreting tumors and clinically non-functioning tumors in MEN-1.DESIGN:We studied six benign insulinomas, four hormone inactive benign neuroendocrine adenomas in MEN-1, and three non-metastatic neuroendocrine carcinomas with clinically symptomatic insulin secretion.METHODS:Endosonography was performed using Pentax FG 32 UA endosonoscope with a longitudinal 7.5 MHz sector array.RESULTS:Tumor diameter was larger in malignant tumors (19 - 70 / 47.0 +/- 25.9 mm) than in benign lesions (2.3 - 19 / 9.7 +/- 5.8 mm). Hypoechoic echogeneity was more or less present in benign and in malignant tumors and could not be used as a criteria for differential diagnosis. Heterogeneous or multinodular structure on endosonographic imaging however, was an exclusive feature of malignant tumors. Echo-free areas representing cystic transformation or necrosis and vascular invasion were additional signs of malignancy.CONCLUSIONS:Molecular genetic diagnosis of MEN-1 and new therapeutic developments such as endoscopic surgery make sufficient imaging procedures in the management of neuroendocrine pancreatic tumors mandatory. Besides valid detection and exact localization, endosonography provides criteria for benign and malignant tumors and thus may be helpful in planning therapeutic strategies.

Aim The aim of the study was to investigate the influence of isolated small nerve fibre dysfunction on microvascular skin blood flow and transcutaneous oxygen tension in patients with diabetes mellitus.Methods Small nerve fibre dysfunction was assessed by the measurement of thermal and pain perception thresholds. Patients with evidence of large fibre disturbances as evaluated by means of vibration perception threshold were excluded from the study. Microvascular blood flow was investigated with laser-Doppler-fluxmetry (LDF) following stimulation with acetylcholine and mild thermal injury.Results Diabetic patients with small nerve fibre injury showed a significantly reduced increase in the laser-Doppler-flux signal following the application of acetylcholine compared with patients without neuropathy or healthy control subjects (2.8 arbitrary units (AU) (1.3-5.5) vs. 7.2 AU (4.1-25.5); P = 0.007 and vs. 8.5 AU (3.0-17.0), P = 0.02, respectively). The increase in LDF following thermal injury was also diminished in patients with small nerve fibre dysfunction compared with patients without neuropathy or the control group (29.8 AU (17.2-46.5) vs. 51.2 AU (29.5-93.5); P = 0.02 and vs. 54.6 AU (39.7-97.7); P = 0.004, respectively). In addition, they showed a significantly reduced transcutaneous oxygen tension compared with the other groups (42.9 mmHg (41.6-55.5) vs. 56.1 mmHg (49.2-60.8); P = 0.04 and vs. 59.0 mmHg (54.6-80.3), P = 0.03, respectively).Conclusions Our study confirms an association between small nerve fibre injury and skin microvascular dysfunction. It further underlines the concept of neurovascular disturbances in the pathogenesis of neurotrophic foot ulceration.

The somatostatin analogue 90Y-DOTATOC (yttrium-90 DOTA-D-Phe1-Tyr3-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer 86Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, 111In-DTPA-octreotide (indium-111 DTPA-D-Phe1-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77–186 MBq 86Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with 111In-DTPA-octreotide (110–187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with 90Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%–20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (τorgans) for 90Y-DOTATOC therapy were: τliver 1.59–2.79 h; τspleen 0.07–1.68 h; and τkidneys 0.55–2.46 h (based on 86Y-DOTATOC). These data suggest that dosimetry based on 86Y-DOTATOC and 111In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for 90Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer 86Y-DOTATOC.

Neuroendokrine Tumoren (NET) haben in den letzten 35 Jahren an Häufigkeit zugenommen. Zeitgleich hat sich auch die Prognose der Patienten wesentlich verbessert, da die Mehrzahl dieser Tumoren heutzutage in einem frühen Stadium festgestellt wird.

Carcinoid tumors are rare and slowly growing neuroendocrine tumors of the foregut, midgut and hindgut. Drug therapy is of special importance in patients with inoperable metastasising disease. This palliative therapy is aimed at reduction of the hormone-dependent symptoms and inhibition of tumor growth. Somatostatin analogues, alpha-interferon and various chemotherapeutic agents are used for this purpose. Drug therapy can be supplemented by surgical and radiological intervention through interdisciplinary cooperation of the surgeon, radiologist, endocrinologist and gastroenterologist.