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Robin P F Dullaart, Rindert de Vries, Arie van Tol and Wim J Sluiter

Objective: We tested the extent to which altered plasma adipokine levels may contribute to the increased carotid artery intima-media thickness (IMT) associated with type 2 diabetes mellitus and with male gender, independently of conventional cardiovascular risk factors, insulin resistance, and plasma C-reactive protein (CRP).

Design: IMT (mean of three segments of both carotid arteries by ultrasonography), insulin resistance (homeostasis model assessment; HOMAir), plasma CRP, lipids, adiponectin, leptin, resistin, and tumor necrosis factor-α (TNF-α) were measured in 84 type 2 diabetic patients and 85 control subjects.

Results: In diabetic patients, IMT (P<0.001), mean arterial pressure (P<0.001), HOMAir (P<0.001), plasma CRP (P=0.003), triglycerides (P=0.037), leptin (P=0.023), resistin (P=0.003), and TNF-α (P=0.003) levels were higher, whereas high-density lipoproteins (HDL) cholesterol (P<0.001) and adiponectin (P<0.001) levels were lower compared with control subjects. Plasma adiponectin (P<0.001) and leptin (P<0.001) were substantially lower in men than in women. IMT was positively and independently associated with age (P<0.001), diabetes (P=0.049), and male gender (P=0.002) in a multivariate regression model, not including other variables. Further analyses showed that IMT was positively related to age (P<0.001) and plasma triglycerides (P=0.038) and negatively to adiponectin (P<0.001), without independent effects of diabetes, gender, and HOMAir.

Conclusions: Increased IMT in type 2 diabetes may in part be explained by lower plasma adiponectin and higher triglycerides, but not by leptin, resistin, and TNF-α. The gender effect on IMT is related to lower plasma adiponectin.

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Geert Tjeerdsma, Wim J Sluiter, Joffre M Hew, Willemina M Molenaar, Willem E de Lange and Robin PF Dullaart

Tjeerdsma G, Sluiter WJ, Hew JM, Molenaar WM, de Lange WE, Dullaart RPF. Hyperprolactinaemia is associated with a higher prevalence of pituitary—adrenal dysfunction in non-functioning pituitary macroadenoma. Eur J Endocrinol 1996;135:299—308. ISSN 0804–4643

In non-functioning pituitary macroadenoma (NFMA), hyperprolactinaemia (hyperPRL) is considered to be a sign of hypothalamic—pituitary dysregulation, but it is unknown whether hyperPRL is associated with an increased frequency of pituitary hormone deficiencies. Forty consecutive patients with histology-proven NFMA were studied and hyperPRL was defined as serum prolactin (PRL) >200 mIU/l in men and >600 mIU/l in women. The pituitary—adrenal axis was evaluated by measurement of urinary free cortisol (N = 38), peak cortisol to insulin-induced hypoglycaemia (IIH, N = 36) and to human corticotrophin-releasing hormone (hCRF, N = 40) and by urinary tetrahydro11-deoxycortisol (H4S, N = 39), plasma androstenedione increment (N = 39) and serum 11-deoxycortisol (N = 1) after metyrapone. Central hypothyroidism, gonadotrophin deficiency and growth hormone (GH) reserve were also assessed. Twenty patients had hyperPRL (serum PRL 331 (2231120)mIU/l (median, range) in men and 932 (660–3927)mIU/l in women); urinary free cortisol excretion (p < 0.03) and peak serum cortisol in response to IIH (p < 0.02) were lower in hyperPRL than in normoPRL patients; peak serum cortisol after hCRF was not different between groups but occurred later in hyperPRL patients (at 60 vs 30 min, p < 0.03); urinary H4S excretion and androstenedione response after metyrapone were lower in hyperPRL than in normoPRL patients (p < 0.05 for both); 60% of hyperPRL patients and 15% of normoPRL patients had an abnormal H4S response (p < 0.025); central hypothyroidism (overt + subclinical) was present in 74% of hyperPRL and in 60% of normoPRL patients (NS); 78% of hyperPRL and 55% of normoPRL patients had gonadotrophin deficiency (NS); growth hormone (GH) deficiency was present in 83% of hyperPRL and in 89% of normoPRL patients (NS); 73.3% of 75 evaluable pituitary hormone axes were abnormal in hyperPRL patients compared to 5 3.8% of 78 hormone axes in normoPRL patients (by metyrapone test to examine adrenal function, p < 0.025); and no significant differences in tumour grade and stage distribution were found between hyperPRL and normoPRL patients. It is concluded that hyperprolactinaemia in NFMA is associated with a higher prevalence of pituitary–adrenal dysfunction, which is likely to be explained at least in part by functional hypothalamic–pituitary interruption.

RPF Dullaart. Department of Endocrinology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Stan Benjamens, Robin P F Dullaart, Wim J Sluiter, Michiel Rienstra, Isabelle C van Gelder and Thera P Links

Objective

Amiodarone is used for the maintenance of sinus rhythm in patients with arrhythmias, but thyroid dysfunction (amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)) is a common adverse effect. As the onset of AIT and AIH may be unpredictable, the value of long-term regular monitoring of amiodarone treated patients for thyroid dysfunction is still uncertain.

Design

We retrospectively documented the frequency at which overt thyroid dysfunction was preceded by subclinical thyroid dysfunction.

Methods

We included 303 patients treated with amiodarone between 1984 and 2007. AIT was defined as a lowered TSH level with an elevated free thyroxine (FT4) and AIH was defined as an elevated TSH level with a decreased or subnormal FT4. Subclinical AIT was defined as a lowered TSH level with a normal FT4 and subclinical AIH as an elevated TSH level with a normal FT4.

Results

200 men and 103 women, aged 62 ± 12.0 years, suffering from atrial (260) or ventricular (43) arrhythmias, were evaluated. During a median follow-up of 2.8 (1.0–25) years, 44 patients developed AIT and 33 AIH. In 42 (55%) patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT or subclinical AIH. In 35 (45%) patients, AIT/AIH was preceded by subclinical AIT or subclinical AIH (16/44 for AIT and 19/33 for AIH).

Conclusions

In a considerable proportion of patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT/AIH. Less than half of the patients with a subclinical event subsequently developed overt AIT/AIH. This study provides data to reconsider the yield of regular testing of thyroid function to predict overt thyroid dysfunction in amiodarone treated patients.

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Robin P F Dullaart, Albert K Groen, Geesje M Dallinga-Thie, Rindert de Vries, Wim J Sluiter and Arie van Tol

Objective

We tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol.

Design

In 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor.

Results

Apo E, PLTP activity, EST, and CET were higher (P=0.04 to <0.001), whereas adiponectin was lower in MetS subjects (P<0.01). Pre-β-HDL and pre-β-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8±1.0 vs 8.5±0.9%, P=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (P<0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status.

Conclusions

The ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.

Free access

Robin P F Dullaart, Gerrit van den Berg, Aafke M van der Knaap, Janneke Dijck-Brouwer, Geesje M Dallinga-Thie, Peter M J Zelissen, Wim J Sluiter and André P van Beek

Objective

GH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important in HDL metabolism. We determined the extent to which the changes in HDL-C in response to GH replacement are predicted by the −629C>A CETP promoter polymorphism, and questioned whether this association is modified by concomitant glucocorticoid treatment.

Design and methods

A total of 91 GH-deficient adults (63 receiving glucocorticoids) were genotyped for the −629 CETP C>A polymorphism. Fasting serum lipids were measured before and after 1.2±0.4 years of GH treatment (Genotropin, Pfizer Inc., Stockholm, Sweden).

Results

In the whole group, total cholesterol and LDL-C decreased (P<0.05) after GH treatment, but the changes in HDL-C were not significant. In CC carriers receiving glucocorticoids (n=19), HDL-C rose by 0.15±0.25 mmol/l (P=0.02; P<0.03 from unchanged HDL-C in −629 AA+CA carriers on glucocorticoids and from CC homozygotes not receiving glucocorticoids). Multivariate regression analysis showed that individual changes in HDL-C were predicted by the CETP polymorphism (CC versus AA+CC, P=0.006) in glucocorticoid users, independently of baseline HDL-C and other variables including apolipoprotein E4 carrier status; an opposite association with the CETP polymorphism was found in patients not receiving glucocorticoids (P=0.053).

Conclusions

We suggest a common CETP variant-glucocorticoid treatment interaction concerning the effect of GH replacement on HDL-C. This may explain some of the reported variation in the HDL-C response to GH.

Free access

Ha T T Phan, Pieter L Jager, Jacqueline E van der Wal, Wim J Sluiter, John T M Plukker, Rudi A J O Dierckx, Bruce H R Wolffenbuttel and Thera P Links

Objective

This retrospective study describes the role of serum thyroglobulin (Tg) in relation to tumor characteristics in the prediction of persistent/recurrent disease in patients with differentiated thyroid cancer (DTC) with negative Tg at the time of ablation.

Design

Between 1989 and 2006, 94 out of 346 (27%) patients with DTC had undetectable Tg at the time of 131I ablation and were included in this evaluation. The group of 94 patients consisted of 15 males and 79 females in the age range of 16–89 years with a median follow-up of 8 years (range 1–17). All medical records and follow-up parameters of the 94 patients were evaluated for the occurrence of persistent/recurrent disease. In patients with persistent/recurrent disease hematoxylin-eosin-stained slides of the primary tumors and/or metastatic lesions were also reviewed for histological features including immunostains for Tg.

Results

During follow-up, 8 out of 94 (8.5%) patients showed persistent/recurrent disease: in the course of the disease two patients showed Tg positivity, three showed Tg antibody (TgAb) positivity, and the other three showed persistently undetectable Tg and TgAb. Patients who developed Tg and/or TgAb positivity during follow-up had a significantly shorter disease-free survival period when compared with patients with persistently undetectable Tg and TgAb (P<0.006). Histological features were not able to predict the recurrent status.

Conclusions

Follow-up of Tg and TgAb in patients with initially negative Tg and TgAb is useful since a number of patients had shown detectable Tg or TgAb during follow-up indicative for persistent/recurrent disease. Tg and TgAb negativity at the time of ablation is not a predictive determinant for future recurrent status.

Free access

Mark R Postma, Romana T Netea-Maier, Gerrit van den Berg, Jens Homan, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus and André P van Beek

Objective

To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly.

Design

This is a cross-sectional study in two tertiary referral centers in The Netherlands.

Patients and methods

One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS.

Results

IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA−, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA.

Conclusion

QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.

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Sophie J van Asselt, Adrienne H Brouwers, Hendrik M van Dullemen, Eric J van der Jagt, Alfons H Bongaerts, Klaas P Koopmans, Ido P Kema, Bernard A Zonnenberg, Henri J Timmers, Wouter W de Herder, Wim J Sluiter, Elisabeth G de Vries and Thera P Links

Background

Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and 11C-5-hydroxytryptophan positron emission tomography (11C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients.

Methods

We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and 11C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard.

Results

In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with 11C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9–55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1–30).

Conclusions

EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.11C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.

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Mark R Postma, Thalijn L C Wolters, Gerrit van den Berg, Antonius E van Herwaarden, Anneke C Muller Kobold, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus, Romana T Netea-Maier and André P van Beek

Objective

To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery.

Design

A retrospective study in two large tertiary referral centers in The Netherlands.

Methods

Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit.

Results

In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006).

Conclusions

Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.