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O M Dekkers, J M Timmermans, J W A Smit, J A Romijn and A M Pereira

Objectives

To compare the cortisol response of the 1 μg and the 250 μg ACTH test in a large study of patients with suspected adrenal insufficiency.

Design

Retrospective cohort study.

Methods

Single center study assessing patients tested for primary or secondary adrenal insufficiency between January 2004 and December 2007, who had both ACTH tests (1 μg and 250 μg; n=207) within a time interval of 6 weeks. Test results were compared with a Bland–Altman plot and McNemar's test.

Results

The mean difference between the cortisol responses in the two ACTH tests was 26 nmol/l (95% confidence interval (CI) 13, 40), showing a marginally higher response for the 250 μg test. The diagnostic performances of the two tests were similar (P=0.49) using a cut-off value for cortisol of 550 nmol/l. A normal cortisol response to the 1 μg ACTH test could be accompanied by an abnormal response to the 250 μg ACTH test, and vice versa.

Conclusion

This study shows that the 1 μg and the 250 μg ACTH tests have comparable cortisol responses in patients with suspected adrenal insufficiency. However, in individual patients, the difference in cortisol response to the two tests can be substantial, and the response in the 250 μg test is not invariably higher than the response in a 1 μg test.

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O M Dekkers, S Hammer, R J W de Keizer, F Roelfsema, P J Schutte, J W A Smit, J A Romijn and A M Pereira

Objective: The natural history of non-functioning pituitary macroadenomas (NFMA) has not been completely elucidated. Therefore, we evaluated pituitary function, visual fields, and tumor size during long-term follow-up of non-operated patients with NFMA.

Design: Follow-up study.

Patients: Twenty-eight patients (age 55 ± 3 years) with NFMA, not operated after initial diagnosis, were included.

Results: Initial presentation was pituitary insufficiency in 44%, visual field defects in 14%, apoplexy in 14%, and chronic headache in 7% of the patients. The duration of follow-up was 85 ± 13 months. Radiological evidence of tumor growth was observed in 14 out of 28 patients (50%) after duration of follow-up of 118 ± 24 months. Six patients (21%) were operated, because tumor growth was accompanied by visual field defects. Visual impairments improved in all the cases after transsphenoidal surgery. Spontaneous reduction in tumor volume was observed in eight patients (29%). No independent predictors for increase or decrease in tumor volume could be found by regression analysis.

Conclusion: Observation alone is a safe alternative for transsphenoidal surgery in selected NFMA patients, without the risk of irreversibly compromising visual function.

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A de Rooij, J P Vandenbroucke, J W A Smit, M P M Stokkel and O M Dekkers

Background

Despite the long experience with radioiodine for hyperthyroidism, controversy remains regarding the optimal method to determine the activity that is required to achieve long-term euthyroidism.

Objectives

To compare the effect of estimated versus calculated activity of radioiodine in hyperthyroidism.

Design

Systematic review and meta-analysis.

Methods

We searched the databases Medline, EMBASE, Web of Science, and Cochrane Library for randomized and nonrandomized studies, comparing the effect of activity estimation methods with dosimetry for hyperthyroidism. The main outcome measure was the frequency of treatment success, defined as persistent euthyroidism after radioiodine treatment at the end of follow-up in the dose estimated and calculated dosimetry group. Furthermore, we assessed the cure rates of hyperthyroidism.

Results

Three randomized and five nonrandomized studies, comparing the effect of estimated versus calculated activity of radioiodine on clinical outcomes for the treatment of hyperthyroidism, were included. The weighted mean relative frequency of successful treatment outcome (euthyroidism) was 1.03 (95% confidence interval (CI) 0.91–1.16) for estimated versus calculated activity; the weighted mean relative frequency of cure of hyperthyroidism (eu- or hypothyroidism) was 1.03 (95% CI 0.96–1.10). Subgroup analysis showed a relative frequency of euthyroidism of 1.03 (95% CI 0.84–1.26) for Graves' disease and of 1.05 (95% CI 0.91–1.19) for toxic multinodular goiter.

Conclusion

The two main methods used to determine the activity in the treatment of hyperthyroidism with radioiodine, estimated and calculated, resulted in an equally successful treatment outcome. However, the heterogeneity of the included studies is a strong limitation that prevents a definitive conclusion from this meta-analysis.

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Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W A Smit, Jeroen J Bax and Richard A Feelders

Objective

In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function.

Methods

In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured.

Results

At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (−16.5±3.5 vs −19.7±3.4%, P=0.013) and longitudinal (−15.9±1.9 vs −20.1±2.3%, P<0.001) directions and decreased SRIVRT (0.3±0.15 vs 0.4±0.2/ s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized.

Conclusion

CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess.

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A A van der Klaauw, J A Romijn, N R Biermasz, J W A Smit, J van Doorn, O M Dekkers, F Roelfsema and A M Pereira

Context: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement.

Patients and methods: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued.

Results: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 ± 0.5 mmol/l at baseline vs 1.7 ± 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 ± 0.7 mmol/l to 5.0 ± 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged.

Conclusion: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.

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L T van Hulsteijn, A Louisse, B Havekes, A A Kaptein, J C Jansen, F J Hes, J W A Smit and E P M Corssmit

Context

Germline mutations in succinate dehydrogenase (SDH) genes predispose carriers for developing paragangliomas, and studies on their quality of life (QoL) are scarce.

Objectives

The objectives of this study were to assess QoL in patients with paragangliomas (PGL), to evaluate long-term QoL, and to explore potential differences in QoL between SDH mutation carriers and paraganglioma patients without an SDH mutation.

Design

Cross-sectional, case–control study.

Setting

Tertiary referral center.

Subjects

One hundred and seventy four paraganglioma patients were included: 25 SDHB, two SDHC, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. They provided 100 peers as control persons. Furthermore, patients were compared with age-adjusted reference populations.

Main outcome measures

QoL was assessed using three validated health-related QoL questionnaires: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Index 20, and the Short Form 36.

Results

Patients reported a significantly impaired QoL compared with their own controls, mainly on fatigue and physical condition subscales. Compared with age-adjusted literature values, patients had significantly impaired scores on physical, psychological, and social subscales. A decreased QoL was mainly related to paraganglioma-associated complaints.

There was no difference in QoL between the various SDH mutation carriers or paraganglioma patients without an SDH mutation. QoL in asymptomatic mutation carriers, i.e. without manifest disease, did not differ from QoL of the general population. Long-term results in 41 patients showed no alteration in QoL besides a reduced level of activity.

Conclusion

QoL is decreased in paraganglioma patients but stable when measured over time.

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K M J A Claessen, S R Ramautar, A M Pereira, J W A Smit, F Roelfsema, J A Romijn, H M Kroon, M Kloppenburg and N R Biermasz

Objective

Arthropathy is an invalidating complication of acromegaly, of which the prognosis and determinants are currently unknown in treated acromegaly. Therefore, the objective of the present study was to investigate the radiographic progression of arthropathy over a mean follow-up period of 2.6 years and determinants of outcome in patients with long-term, well-controlled acromegaly.

Design

Prospective follow-up study.

Methods

In a prospective cohort study we studied 58 patients (mean age 62, women 41%) with controlled acromegaly for a mean of 17.6 years. Radiographic progression of joint disease was defined by the Osteoarthritis Research Society International classification as a 1-point increase in joint space narrowing (JSN) or osteophyte scores on radiographs of the hands, knees, and hips obtained at the first study visit and after 2.6 years. Potential risk factors for progression were assessed.

Results

Progression of osteophytes and JSN was observed in 72 and 74% of patients respectively. Higher age predisposed for osteophyte progression. Patients with biochemical control by somatostatin (SMS) analogs had more progression of osteophytosis than surgically cured patients (odds ratio=18.9, P=0.025), independent of age, sex, BMI, baseline IGF1 SDS and exon 3 deletion of the GHR. This was also evident for JSN progression, as were higher age and higher baseline IGF1 SDS.

Conclusions

Acromegalic patients have progressive JSN and osteophytosis, despite long-term biochemical control. Parameters reflecting GH/IGF1 activity were associated with progressive joint disease. Remarkably, biochemical control by SMS analogs was associated with more progression than surgical cure. Although the present study is not a randomized controlled trial, this may indicate insufficient GH control according to current criteria and the need for more aggressive therapy.

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N E Kokshoorn, J W A Smit, W A Nieuwlaat, J Tiemensma, P H Bisschop, R Groote Veldman, F Roelfsema, A A M Franken, M J E Wassenaar, N R Biermasz, J A Romijn and A M Pereira

Objective

Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, such as timing of evaluation and the severity of the trauma.

Aim

To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation.

Study design

Cross-sectional study.

Patients and methods

We included 112 patients with TBI, hospitalized for at least 3 days and duration of follow-up >1 year after TBI from five (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (n=90) or, when contraindicated, ACTH stimulation and/or CRH stimulation tests and a GH releasing hormone–arginine test (n=22). Clinical evaluation included quality of life questionnaires.

Results

We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m2. Mean duration of hospitalization was 11 (3–105), and 33% of the patients had a severe trauma (Glasgow Coma Scale <9) after TBI. The mean duration of follow-up was 4 (1–12) years.

Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe GH deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (P=0.002).

Conclusion

In this study, the prevalence of hypopituitarism during long-term follow-up after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI.

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T C Schneider, R M Abdulrahman, E P Corssmit, H Morreau, J W A Smit and E Kapiteijn

Objective

We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented.

Patients and methods

Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity.

Results

Median PFS was 18 months (95% confidence interval (95% CI): 7–29 months) and median OS was 34.5 months (95% CI: 19–50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5–39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash.

Conclusion

Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.

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O M Dekkers, N R Biermasz, J W A Smit, L E Groot, F Roelfsema, J A Romijn and A M Pereira

Objective: Quality of life (QoL) has become increasingly important in the evaluation of treatment of pituitary and hormonal diseases. A reduced QoL has been reported in childhood-onset craniopharyngioma; however, reports of QoL in adult craniopharyngioma patients are scarce. In the present study, we assessed QoL in adult patients successfully treated for craniopharyngioma in our centre.

Design: This was a case-control study.

Methods: In this study, we assessed QoL in 29 adult patients in remission during long-term follow-up after treatment for craniopharyngioma. Four validated health-related questionnaires (HADS, MFI-20, NHP and SF-36) were used, covering multiple aspects of physical, psychological and social functioning. Patient outcomes were compared to controls (n = 142) and to age-adjusted reference values derived from literature.

Results: General fatigue, physical fatigue, energy, physical condition and physical mobility were significantly impaired, compared with controls. The main independent predictors for decreased QoL were visual field defects (depression, total HADS score, activity, motivation and energy), female gender (depression, motivation and pain), repeat surgery (role limitations due to emotional problems) and radiotherapy (mental fatigue) (the last two predictors to a lesser extent).

Conclusion: Adult patients treated for craniopharyngioma show persistent impairment in QoL, especially in the physical subscales.