Pierre Zelissen

Incidence of Venous Thromboembolism in Patients with Cushing's Syndrome: A Multicenter Cohort Study

CONTEXT Venous thrombosis has frequently been reported in patients with endogenous Cushings syndrome (CS). OBJECTIVE The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe.

Background Conventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring. Objectives i) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations. Methods The review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment. Results Optimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs. Conclusions This review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.

The hypercoagulable state in Cushing's disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy.

CONTEXT Cushings disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.

Calcitonin gene-related peptide in human obesity

We studied plasma calcitonin gene-related peptide (CGRP) levels in obese women before (n = 24) and after (n = 13) weight loss, and in normal weight controls (n = 15). Furthermore, the influence of two isocaloric meals (high carbohydrate vs. high fat) on plasma CGRP concentrations was studied. The CGRP concentration in the obese group (32.26 +/- 2.01 pg/ml) was significantly (p less than 0.0001) higher than in the control group (21.64 +/- 0.15 pg/ml). After weight loss (14.3 +/- 0.72% of original weight) CGRP concentrations remained unchanged. Only the high-fat meal caused a significant (p less than 0.02) rise in CGRP levels. Our results indicate that elevated plasma CGRP levels may constitute a primary phenomenon in obese women, and that fat intake may be associated with increased CGRP secretion.

Fixed dosage of 131I for remnant ablation in patients with differentiated thyroid carcinoma without pre-ablative diagnostic 131I scintigraphy.

Differentiated thyroid cancer is treated by (near) total thyroidectomy followed by radioiodine (131I) ablation of the residual active tissue in the thyroid bed. Controversy remains concerning the use and the dose of pre-ablative diagnostic 131I scintigraphy. This study was designed to assess the efficacy of thyroid ablation by high-dose 131I without pre-ablative diagnostic 131I scintigraphy. Ninety-three patients were treated with (near) total thyroidectomy and with a high ablative dose of 131I (3700-7400 MBq). A pre-ablative 131I diagnostic scintigram was not performed. To assess the efficacy of the treatment, all patients were studied with a diagnostic 131I scintigram and with thyroglobulin plasma assays 1 year later after withdrawal of L-thyroxine for 4-6 weeks. The main criterion for a successful ablation was the absence of thyroid bed activity. An additional criterion was a thyroglobulin value of <10 μg·l−1. Successful ablation according to the main criterion was obtained in 88% of patients. Forty patients (43%) showed no neck uptake and had undetectable serum thyroglobulin. Twenty-two patients (25%) had serum thyroglobulin concentrations between 1 and 10 μg·−1. Twenty-six patients (27%) had thyroglobulin >10 μg·l−1, 19 patients showing residual thyroid uptake or metastatic lesions. We conclude that high-dose radioiodine ablation without prior diagnostic scintigraphy results in a high rate of successful ablation, preventing repeat 131I treatment.

GIP-dependent adrenal Cushing's syndrome with incomplete suppression of ACTH

ACTH‐independent Cushings syndrome may be due to the development of ectopic hormone receptors in adrenal tissue. Thus, in food‐dependent Cushings syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the case of a 60‐year‐old woman with food‐dependent Cushings syndrome whose cortisol levels increased after stimulation with CRH. In this patient with Cushings syndrome the finding of low basal plasma cortisol levels in the late night and early morning as well as a paradoxical rise of plasma cortisol during a 7‐h infusion with dexamethasone (carried out without any restriction in food intake), suggested that cortisol production was stimulated at times of food intake. Hourly measurements of plasma cortisol for 48 h revealed prominent meal‐related peaks. A plasma cortisol response, elicited by oral glucose administration, could be prevented by octreotide. Plasma ACTH was low or undetectable. CRH administration was followed by a ACTH response from 3 to 16 ng/l and a plasma cortisol response from 230 to 680 nmol/l. Octreotide treatment for nearly five months induced a partial clinical and biochemical remission. Total bilateral adrenalectomy was performed. The left adrenal was grossly enlarged (7 × 5.5 × 4 cm) and the right adrenal was slightly enlarged (6 × 4 × 1.8 cm). Microscopy revealed bilateral nodular hyperplasia. Cell suspensions of adrenal tissue from the patient did respond in a dose‐dependent fashion to stimulation with GIP and were very sensitive to stimulation with synthetic ACTH1–24. However, CRH had no significant effect on cortisol production in vitro. Using RT‐PCR amplification and cDNA hybridization, GIP receptor was found to be overexpressed in the left and right adrenal tissues from this patient as compared to adrenal tissues from a normal individual or from non GIP‐dependent adrenal Cushings syndrome. There was no evidence of presence of adrenal CRH receptors. Thus, in this patient with food‐dependent Cushings syndrome, the CRH‐induced plasma ACTH and cortisol response is probably mediated by an incomplete suppression of the HPA axis as a result of the intermittent food‐dependent nature of Cushings syndrome.

Magnetic Resonance Imaging–Assessed Adipose Tissue and Serum Lipid and Insulin Concentrations in Growth Hormone–Deficient Adults Effect of Growth Hormone Replacement

The visceral and subcutaneous abdominal adipose tissue (AT) areas and the subcutaneous hip AT area were assessed by magnetic resonance imaging (MRI) in relation to serum lipid and plasma insulin levels in 12 growth hormone-deficient (GHD) adults before and after 6 months of replacement therapy with recombinant human growth hormone (rhGH) and in 12 healthy control subjects. Compared with control subjects, GHD patients had a significantly increased amount of visceral AT, which was inversely related with plasma HDL cholesterol and positively correlated with plasma triglyceride levels. Visceral AT was not associated with plasma total and LDL cholesterol or plasma insulin concentrations. GHD patients also had elevated serum total cholesterol, LDL cholesterol, and triglyceride levels compared with control subjects. After 6 months of rhGH replacement therapy the mean visceral, subcutaneous abdominal, and subcutaneous hip AT areas and serum concentration of total cholesterol decreased significantly, whereas serum HDL cholesterol concentration increased significantly. No significant correlations were found between changes in the amount of AT and changes in serum lipid and plasma insulin levels.

Fluorine-18 fluorodeoxyglucose dual-head positron emission tomography in the detection of recurrent differentiated thyroid cancer: preliminary results

Abstract. In the follow-up of patients with thyroid cancer, it may be very difficult to identify the site of recurrence in the presence of persistently elevated or rising thyroglobulin (Tg) levels and negative iodine-131 whole-body scintigraphy (WBS). The aim of this study was to assess the feasibility of employing fluorine-18 fluorodeoxyglucose and a dual-head positron emission tomography (PET) camera to detect recurrent thyroid cancer in patients with elevated Tg levels and negative 131I WBS. Eleven patients suspect of having recurrent thyroid cancer (five males, six females; mean age 47 years; range 26–73 years) were studied with both 131I WBS and FDG using a dual-head PET camera. The suspicion that these patients had recurrent thyroid cancer was based on elevated Tg levels. Thyroid stimulating hormone (TSH) and Tg levels as well as antibodies to Tg were measured 3 weeks after the withdrawal of tri-iodothyronine. In patients in whom pathological uptake was seen on the PET images but who had no signs of recurrent thyroid cancer on WBS, ultrasonography and/or computed tomography or magnetic resonance imaging was performed followed by fine-needle aspiration cytology. The mean Tg and TSH levels after discontinuation of l-thyroxine were 156 ng/ml (range 4–815 ng/ml) and 84 mU/l (range 43–159 mU/l), respectively. None of the patients had antibodies to thyroglobulin. In seven out of ten patients with negative 131I WBS, FDG PET showed focally increased uptake in the head and neck region. In one patient, the site of increased uptake on the PET images corresponded with the site of increased 131I uptake. Malignancies with a diameter less than 1 cm (n=3) were not depicted by either CT or US. It is concluded that detection of recurrent thyroid cancer by means of FDG dual-head PET is feasible in patients with elevated Tg concentrations and negative 131I WBS. The results justify a prolongation of the study.

The paradoxical nature of sexuality in anorexia nervosa

Psychosexual dysfunctioning is often put forward as an etiological factor in anorexia nervosa. In contrast, we hypothesize that anorexia nervosa patients were in general psychosexually normal before their illness, and that the problems in their sexual life arise only after the emergence of hypogonadism, as a consequence of emaciation. Our study shows that patients, before they became anorectic, were indeed rather similar to normal subjects with respect to sexual attitude. Moreover, patients reported a considerably decreased sexual interest during their anorectic period when compared with normal controls. We conclude that these results corroborate our hypotheses. In the discussion we sketch a theoretical account of the origin and course of anorexia nervosa, according to which the hormonal and associated psychosexual changes are central to its pathogenesis.

The Role of Routine Diagnostic Radioiodine Whole-Body Scintigraphy in Patients with High-Risk Differentiated Thyroid Cancer

Follow-up diagnostic radioiodine whole-body scintigraphy (DxWBS) is still advised for high-risk patients with differentiated thyroid cancer. The aim of this study was to evaluate the additional value of DxWBS to stimulated thyroglobulin measurement in high-risk patients. Methods: The results of DxWBS and thyroglobulin measurements performed 6–12 mo after surgery and radioiodine thyroid remnant ablation in patients with differentiated thyroid cancer were retrospectively evaluated for 112 patients with high-risk features for recurrence (R3/T4 and N1). Results: One patient had an undetectable thyroglobulin level, with DxWBS results suggestive of cervical recurrence. DxWBS was found to be false-positive. Of the patients with detectable thyroglobulin levels, the DxWBS results were negative in 65 and positive in only 8. The 6 patients positive for thyroglobulin antibody had negative DxWBS results. The remaining patients had an undetectable thyroglobulin level and negative DxWBS results. Conclusion: Because undetectable stimulated thyroglobulin levels have a negative predictive value of 100%, DxWBS offers no information additional to recombinant human thyroid-stimulating hormone–stimulated thyroglobulin measurements in patients with high-risk differentiated thyroid cancer.