18F-fluoro-ethyl-tyrosine PET co-registered with MRI in patients with persisting acromegaly.

OBJECTIVE: To report our experience with 18F-fluoro-ethyl-tyrosine (FET) positron emission tomography-computed tomography (PET-CT) co-registered with magnetic resonance imaging (MRI) (FET-PET/MRICR) in the care trajectory for persistent acromegaly. DESIGN: Prospective case series. PATIENTS: Ten patients with insufficiently controlled acromegaly referred to our team to evaluate surgical options. MEASUREMENTS: FET-PET/MRICR was used to support decision-making if MRI alone and multidisciplinary team evaluation did not provide sufficient clarity to proceed to surgery. RESULTS: FET-PET/MRICR showed suspicious (para)sellar tracer uptake in all patients. In five patients FET-PET/MRICR was fully concordant with conventional MRI, and in one patient partially concordant. FET-PET/MRICR identified suggestive new foci in four other patients. Surgical re-exploration was performed in nine patients (aimed at total resection (6), debulking (2), diagnosis (1)), and one patient underwent radiation therapy. In 7 of 9 (78%) operated patients FET-PET/MRICR findings were confirmed intraoperatively, and in six (67%) also histologically. IGF-1 decreased significantly in eight patients (89%). All patients showed clinical improvement. Complete biochemical remission was achieved in three patients (50% of procedures in which total resection was anticipated feasible). Biochemistry improved in five and was unchanged in one patient. No permanent complications occurred. At six months, optimal outcome (preoperative intended goal achieved without permanent complications) was achieved in six (67%) patients and an intermediate outcome (goal not achieved, but no complications) in the other three patients. CONCLUSIONS: In patients with persisting acromegaly without a clear surgical target on MRI, FET-PET/MRICR is a new tracer to provide additional information to aid decision-making by the multidisciplinary pituitary team.

Clinical Characteristics, Diagnostic Approach and Outcome of Thyroid Incidental Findings vs. Clinically Overt Thyroid Nodules: An Observational Single-Centre Study.

Context: Thyroid nodules are common and can present as clinically overt nodules (visible, palpable or symptomatic nodules) and so-called incidentalomas (coincidental findings on imaging techniques). The majority are benign but recognizing clinically relevant nodules remains a challenge. Current Dutch guidelines recommend to refrain from additional diagnostic testing in incidentalomas other than FDG-PET-incidentalomas, unless there are suspicious clinical and/or sonographic features. However, there is no consensus on the further approach and no "real-life" data on the outcome of such an approach. Objective: To compare clinical characteristics, diagnostic approaches and clinical outcome between patients referred with thyroid incidentalomas and non-incidentalomas at one academic referral thyroid clinic. Methods: Clinical and demographical characteristics, diagnostic and therapeutic approaches and outcome were retrospectively obtained from the files of all patients newly referred because of thyroid incidentalomas or non-incidentalomas to our institution (between March 2011 and January 2017). Subsequently, the data were compared between both groups. Results: In total, 351 patients (64.3%) were referred because of non-incidentalomas and 195 (35.7%) because of incidentalomas. Incidentalomas were smaller (48.7% <2 cm) than non-incidentalomas (23.4% <2 cm). Furthermore, incidentalomas were less often symptomatic (15.9 vs. 42.7% p < 0.001). Fine-needle aspiration was performed in a similar percentage of the patients in the two groups (62.6% of incidentalomas vs. 69.8% in non-incidentaloma, p = 0.08). Significantly less malignancies were found among incidentalomas compared to non-incidentalomas (5.1% vs. 11.1%, p = 0.019). Moreover, significantly more malignancies occurred in PET-incidentalomas than non-PET-incidentalomas (11.8% vs. 2.8%, p = 0.023). In fact, the proportion of malignancies in PET-incidentalomas and non-incidentalomas was similar (11.8% vs. 11.1%, p = 0.895). Stability or decrease in size was observed in 96.5% of nodules receiving ultrasound follow-up. Conclusions: Patients with small asymptomatic thyroid incidentalomas represent an important proportion of the patients referred for additional diagnostic evaluation. The risk of malignancy in these patients is lower than in those with symptomatic palpable lesions, particularly in the patients with incidentalomas discovered on CT, MRI or US. Our findings support the current recommendations from the Dutch guidelines to not indiscriminately perform additional analysis and treatment on all incidentalomas, but prioritize this to FDG-PET-incidentalomas and clinically relevant non-PET-incidentalomas. Moreover, US features can further refine the selection of the patients who require immediate FNAC and/or surgery.

A multidisciplinary care pathway improves quality of life and reduces pain in patients with fibrous dysplasia/McCune-Albright syndrome: a multicenter prospective observational study.

BACKGROUND: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care. RESULTS: 92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1-Q3 36-56). Skeletal burden correlated with baseline Physical Function (rs = - 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function (mean 67 ± SD24 to 74 ± 21, effect size (ES) 0.31, p = 0.020), Role Physical (39 ± 41 to 53 ± 43, ES 0.35, p = 0.066), Social Functioning (64 ± 24 to 76 ± 23, ES 0.49, p = 0.054), and Health Change (39 ± 19 to 53 ± 24, ES 0.76, p = 0.016), chronic patients in Physical Function (52 ± 46 to 66 ± 43, ES 0.31, p = 0.023) and Emotional Wellbeing (54 ± 27 to 70 ± 15, ES 0.59, p < 0.001). New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated (rs = - 0.472, p < 0.001). Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function. CONCLUSIONS: All FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers.

Diagnosing pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 in daily practice.

Background: In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs). Methods: Patients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up. Results: A total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0-95.6) and 92.8% (89.4-95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3-96.0) and 85.3% (80.5-89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1-100) and 87.1% (76.3-93.6) and for CT, 60.0% (22.9-88.4) and 70.4% (51.3-84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0-98.8) and 87.0% (75.3-93.9), respectively, for MRI and 100% (74.9-100) and 77.8% (54.3-91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma. Conclusion: As the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA.

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

Initiating Pancreatic Neuroendocrine Tumor (pNET) Screening in Young MEN1 Patients: Results From the DutchMEN Study Group.

CONTEXT: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate. OBJECTIVE: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients. METHODS: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size ≥ 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease. RESULTS: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively. CONCLUSION: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified. The psychological and medical burden of screening at a young age should be considered.

Persistent improvement of bone mineral density up to 20 years after treatment of Cushing's syndrome.

OBJECTIVE: Cushing's syndrome (CS) is associated with osteoporosis and high fracture risk. Besides male sex, it is unknown which variables influence bone mineral density (BMD) at diagnosis and it is unclear to what extent BMD normalizes during long-term follow-up after treatment of CS. The aim of this study was to determine factors associated with BMD at diagnosis of CS and to determine the long-term course of BMD and fracture rate after successful treatment of CS. DESIGN: Retrospective cross-sectional and longitudinal cohort study. METHODS: Data were collected from 231 patients with CS who were treated at the Radboud University Medical Centre between 1968 and 2020. RESULTS: At diagnosis, male sex was associated with lower Z-scores at the lumbar spine (LS) compared with female sex: -0.97s.d. (-1.45 to -0.49) after correction for possible confounders. Shorter duration of symptoms and younger age were also associated with lower Z-scores at diagnosis, while etiology of CS, urinary cortisol excretion and gonadal status were not associated with Z-scores at diagnosis. Z-scores improved up to 20 years after treatment. Fifteen years after treatment, men showed larger improvements of Z-scores than women; +2.56 (1.82-3.30) increase in LS Z-score vs +1.48 (0.96-2.00) respectively. Fracture incidence was highest during the 2 years before diagnosis and decreased after treatment. CONCLUSION: Male sex, younger age and shorter duration of symptoms are associated with lower BMD at diagnosis of CS. BMD continues to improve up to 20 years after treatment of CS. Fracture rate decreases after treatment of CS.

Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study.

Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N-terminal propeptide [P1NP], and ß-crosslaps [B-CTX, also termed ß-C-terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Spontaneous bone infarction of the distal femur in a patient with Cushing's disease: a case report.

Avascular necrosis of the femoral head is a well-known complication of treatment with high dosage glucocorticoids and has been described in a few patients with Cushing's syndrome. In this case report, we describe the, to our knowledge, first case of a patient with endogenous Cushing's syndrome with a bone infarction located in the distal femur. In patients with Cushing's syndrome and bone pain, the diagnosis of bone infarction should be considered as it can occur as a rare complication of hypercortisolism.

The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging. AIM: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up. METHODS: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior. RESULTS: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course. CONCLUSION: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.

Venous thromboembolism in patients with adrenocortical carcinoma after surgery.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with a poor prognosis. We hypothesized that patients with adrenocortical carcinoma are at high risk for venous thromboembolism, given the numerous risk factors such as malignancy, abdominal surgery, immobility and hormonal excess. The aim of this study was to determine retrospectively the incidence of venous thromboembolisms after surgical treatment in patients with adrenocortical carcinoma. MATERIALS AND METHODS: A retrospective study was performed, collecting data from all patients diagnosed with adrenocortical carcinoma from 2003 to 2018 at the Radboud University Medical Centre, The Netherlands. RESULTS: In 34 patients, eight postoperative venous thromboembolisms, all pulmonary embolisms, were diagnosed in the first 6 months after adrenalectomy (23.5%). In addition, one patient developed pulmonary embolism just prior to surgery and one patient 7 years after surgery. Five of the eight patients with postoperative venous thromboembolisms presented with symptomatic pulmonary embolism whereas the other three pulmonary embolisms were incidentally found on regular follow up CT scans. Seven of the eight venous thromboembolisms occurred within 10 weeks after surgery. Seven of the eight patients had advanced stage adrenocortical carcinoma and four patients already received low-molecular weight heparin during the development of the venous thromboembolism. There was one case of fatal pulmonary embolism in a patient with a cortisol producing tumor with pulmonary metastases, despite the use of a therapeutic dose thromboprophylaxis. CONCLUSION: Patients with adrenocortical carcinoma are at high risk of developing postoperative venous thromboembolisms. Prolonged postoperative thromboprophylaxis could be considered in these patients.

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. OBJECTIVE: To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. METHODS: All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. RESULTS: A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. CONCLUSIONS: These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG).

BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

Toward Shorter Hospitalization After Endoscopic Transsphenoidal Pituitary Surgery: Day-by-Day Analysis of Early Postoperative Complications and Interventions.

BACKGROUND: It is unclear which patients have the greatest risk of developing complications in the first days after endoscopic transsphenoidal pituitary surgery (ETS) and how long patients should stay hospitalized after surgery. The objective of this study is to identify which patients are at risk for early postoperative medical and surgical reinterventions to optimize the length of hospitalization. METHODS: The medical records of 146 patients who underwent ETS for a pituitary adenoma between January 2013 and July 2016 were reviewed retrospectively. Data were collected on baseline patient-related characteristics, characteristics of the pituitary adenoma, perioperative complications and interventions, and postoperative outcomes. Patients who underwent additional interventions on days 2, 3, and 4 after ETS were identified as cases, and patients who did not have any interventions after day 1 postoperatively were identified as controls. RESULTS: Diabetes mellitus (odds ratio [OR], 4.279; 95% confidence interval [CI], 1.149-15.933; P = 0.03), incomplete adenoma resection (OR, 2.840; 95% CI, 1.228-6.568; P = 0.02) and increased morning sodium concentration on day 2 after surgery (OR, 5.211; 95% CI, 2.158-12.579; P <0.001) were associated with reinterventions. Patients without interventions on day 1 or 2 had only an 18.6% chance of a reintervention (OR, 0.201; 95% CI, 0.095-0.424). CONCLUSIONS: Patients with diabetes mellitus, incomplete adenoma resection, and increased morning sodium concentration on day 2 after surgery have an increased chance on reinterventions. In addition, patients without any interventions on day 1 and 2 are at low risk for later reinterventions. These patients could be suitable candidates for early hospital discharge.

Thyrotropin versus age relation as an indicator of historical iodine intake.

BACKGROUND: In populations with mild iodine deficiency, the serum level of thyrotropin (TSH) is negatively and the serum free thyroxine (FT4) is positively associated with age. An ongoing decrease of TSH and increase of FT4 can be found after iodine supplementation. The aim of this study was to investigate whether there are current differences in the relation between thyroid function and age in relation to differences in iodine intake in the past. METHODS: Eight medical laboratories in several regions of The Netherlands, which are all iodine sufficient at present but with a difference in iodine status in the past, provided the results of all TSH and FT4 measurements performed from 2006 until 2011, resulting in 330,802 TSH and 103,940 FT4 measurements. RESULTS: The negative association between TSH and age in the elderly is only present in areas with a historical iodine deficiency (regression coefficients [RC] -0.008, 95% confidence interval [CI] -0.009; -0.007). In the historically iodine-sufficient population, TSH shows no obvious increase or decrease with age. In both the historically iodine-sufficient and iodine-deficient populations, FT4 levels were positively associated with age in the elderly (RC 0.009, 95% CI 0.008; 0.010 and RC 0.008, 95% CI 0.007; 0.010, respectively). CONCLUSIONS: There are differences in relation between thyroid function and age between populations with differences in iodine intake in the past, despite an adequate iodine status at present. This raises the question whether the present but also historical iodine status of a population should be taken into account when establishing the reference limits of TSH and FT4.

Associations between thyroid function and mortality: the influence of age.

OBJECTIVE: The aim of this study was to investigate the influence of age on the association between thyroid function and mortality. DESIGN: The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease. METHODS: TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002-2003. The number of deaths were established in 2012 (median follow-up time 9.4 years). RESULTS: Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1-5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5-22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5-15.0 pmol/l): HR 1.7 (95% CI 1.0-2.9). In these elderly, TSH levels within the high-normal range (3.0-4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0-2.0 mIU/l): HR 1.8 (95% CI 1.0-3.1). CONCLUSIONS: The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups.

Longitudinal trends in thyroid function in relation to iodine intake: ongoing changes of thyroid function despite adequate current iodine status.

OBJECTIVE: Several cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past. METHODS: In an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age. RESULTS: within 4 years, TSH decreased by 5.4% (95% ci 2.58.3%) and FT4 increased by 3.7% (95% ci 2.94.6%). median urinary iodine concentration was 130 µg/l. estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4 over time or with the presence of antibodies against thyroid peroxidase. Only FT4 appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17-1.84%) higher FT4 for each lower iodine quintile. CONCLUSIONS: In this longitudinal study, we found an ongoing decrease in TSH and increase in FT4 in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.

Is there a relationship between fatigue perception and the serum levels of thyrotropin and free thyroxine in euthyroid subjects?

BACKGROUND: Thyrotoxicosis and hypothyroidism are associated with fatigue. Here we studied euthyroid subjects to determine if there was a relationship between serum thyrotropin (TSH), free thyroxine (FT(4)) and thyroperoxidase antibodies and fatigue. METHODS: A total of 5897 participants of the Nijmegen Biomedical Study received a questionnaire and serum TSH (normal range 0.4-4.0 mIU/L) and FT(4) (normal range 8-22 pmol/L) were measured. Fatigue was evaluated by the RAND-36 and the shortened fatigue questionnaire (SFQ). RESULTS: Euthyroid subjects with a serum TSH level of 0.4-1.0 mIU/L had a lower RAND-36 vitality score (65.2 vs. 66.8; regression coefficient (RC) -1.6 [95% confidence interval (CI) -2.6 to -0.5]; p=0.005) and a higher SFQ score (11.7 vs. 11.0; RC 0.6 [CI 0.2-1.0]; p=0.004) than those with a TSH of 1.0-2.0 mIU/L. Those with a serum FT(4) of 18.5-22 pmol/L reported fatigue more often (52.5% vs. 33.3%; relative risk (RR) 1.4 [CI 1.0-1.9]; p=0.03), had a lower RAND-36 vitality score (61.7 vs. 66.6; RC -4.4 [CI -8.1 to -0.6]; p=0.02) and a higher SFQ score (13.2 vs. 11.0; RC 1.9 [CI 0.4-3.3]; p=0.01) than subjects with a FT(4) level of 11.5-15 pmol/L. In comparison to euthyroid subjects without known thyroid disease, euthyroid subjects with previously known thyroid disease reported fatigue more often (52.3% vs. 34.0%; RR 1.3 [CI 1.0-1.5]; p=0.025), had a lower RAND-36 vitality score (61.4 vs. 66.3; RC -2.9 [CI -5.3 to -0.6]; p=0.015) and a higher SFQ score (13.7 vs. 11.1; RC 1.4 [CI 0.5-2.3]; p=0.002). CONCLUSION: In euthyroid individuals without a history of thyroid disease, there is a modest relationship between thyroid function and fatigue with subjects having an apparently higher production of T(4) experiencing more fatigue. Subjects with a history of thyroid disease, but with normal TSH and FT(4) concentrations, experience more fatigue than the general population. The reasons for this are unclear, but subtle abnormalities in the dynamics of thyroid hormone secretion should be considered.