Papers by Kristien Boelaert
The Journal of clinical endocrinology and metabolism, Jan 9, 2015
Cushing's syndrome is a severe condition with excess mortality and significant morbidity nece... more Cushing's syndrome is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. To assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with Cushing's syndrome. Retrospective, multicenter. Thirteen university hospitals. 195 patients with proven Cushing's syndrome: 115 Cushing's disease (CD), 37 ectopic ACTH (EAS); 43 ACTH-independent disease (Adrenocortical Cancer [ACC] 10; adrenal adenoma [AA] 30; ACTH-independent adrenal hyperplasia (3) Measurements: Biochemical parameters of activity of Cushing's syndrome: mean serum cortisol day-curve (CDC) (target 150-300nmol/L); 09.00h serum cortisol; 24h-UFC. 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 months, range 3 days to 11.6 years). There were s...
BACKGROUND The diverse effects of hyperthyroidism are responsible for a wide variety of symptoms ... more BACKGROUND The diverse effects of hyperthyroidism are responsible for a wide variety of symptoms . These are related to the multiple effects of thyroid hormone that regulate energy and heat production, and facilitate the development of the central nervous system, somatic growth, puberty, and important hepatic, cardiac, neurologic, and muscular functions . Age plays a major role in the manifestations of hyperthyroidism, regardless of the underlying cause of the syndrome . Perhaps the most extreme example is the absence of symptoms in elderly patients who have apathetic thyrotoxicosis, a syndrome that can barely be recognized as hyperthyroidism . The objective of this study was to determine the prevalence of symptoms and signs of hyperthyroidism according to patient age and sex and the severity and type of hyperthyroidism . METHODS This is a cross-sectional study of 3049 consecutive patients with overt hyperthyroidism, the data from whom were collected from 1984 through September 2006...
Endocrine Research, 2014
Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), an... more Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family. Methods: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing. Results: The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date. Conclusions: This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the aminoterminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.
The Lancet Diabetes & Endocrinology, 2013
Endocrine Abstracts, 2014
European Journal of Endocrinology, 2015
Guideline advice of many Societies on the management of subclinical hypothyroidism in pregnancy s... more Guideline advice of many Societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies in patients with positive thyroid specific antibodies and higher TSH levels which classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of fetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.
Journal of Clinical Research in Pediatric Endocrinology, 2014
©Jo ur nal of Cli ni cal Re se arch in Pe di at ric En doc ri no logy, Pub lis hed by Ga le nos P... more ©Jo ur nal of Cli ni cal Re se arch in Pe di at ric En doc ri no logy, Pub lis hed by Ga le nos Pub lis hing.
The Journal of Clinical Endocrinology & Metabolism, 2015
Background: Graves' disease (GD) as an immune reconstitution inflammatory syndrome (IRIS) during ... more Background: Graves' disease (GD) as an immune reconstitution inflammatory syndrome (IRIS) during highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has previously been reported. However, clinical challenges associated with HIV in the context of Thyroid Eye Disease (TED) are not as well-characterized.
Side Effects of Drugs Annual, 2009
Endocrine Abstracts, 2014
Molecular Carcinogenesis, 2014
The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xen... more The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P ¼ 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (D126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.
Endocrine Abstracts, 2014
Oncogene, 2003
The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition ... more The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11b-hydroxysteroid dehydrogenase (11b-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11b-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11b-HSD2 was readily demonstrable. Here we have used realtime RT-PCR to quantify expression of mRNA for 11 b-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11b-HSDl mRNA compared with normals (0.2-fold, Po0.05). In contrast, expression of 11b-HSD2 mRNA was 9.8-fold greater in tumors than in normals (Po0.001). Enzyme assays showed significant 11b-HSD2 activity (71.9722.3 pmol/h/mg protein (mean7s.d.)) but no detectable 11b-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11b-HSD2 inhibitor) resulted in a 30.377.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11b-HSDl to 11b-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11b-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.
The Journal of Clinical Endocrinology & Metabolism, 2013
Hyperthyroidism is common, but opinions regarding optimal therapy with antithyroid drugs or radio... more Hyperthyroidism is common, but opinions regarding optimal therapy with antithyroid drugs or radioiodine (131-I) differ. There are no randomized trials comparing these options in terms of mortality. The aim of the study was to determine whether mortality associated with hyperthyroidism varies with treatment administered or other factors. We conducted a prospective observational population-based study of 1036 subjects aged ≥ 40 years presenting to a single specialist clinic from 1989-2003 with a first episode of hyperthyroidism who were followed until June 2012. Antithyroid drugs or radioiodine (131-I) were administered. We compared causes of death with age-, sex-, and period-specific mortality in England and Wales and used within-cohort analysis of influence of treatment modality, outcome, disease etiology, severity and control, and comorbidities. In 12 868 person-years of follow-up, 334 died vs 290.6 expected (standardized mortality ratio [SMR], 1.15 [95% confidence interval (CI),1.03-1.28]; P = .01). Increased all-cause mortality largely reflected increased circulatory deaths (SMR, 1.20 [95% CI, 1.01-1.43]; P = .04). All-cause mortality was increased for the person-years accumulated during thionamide treatment (SMR, 1.30 [95% CI, 1.05-1.61]; P = .02) and after 131-I not associated with hypothyroidism (SMR, 1.24 [95% CI, 1.04-1.46]; P = .01) but not during T₄ replacement for 131-I-induced hypothyroidism (SMR, 0.98 [95% CI, 0.82-1.18]; P = .85). Within-cohort analysis comparing mortality during thionamide treatment showed a similar hazard ratio (HR) for all-cause mortality when 131-I did not result in hypothyroidism (HR, 0.95 [95% CI, 0.70-1.29]), but reduced mortality with 131-I-induced hypothyroidism (HR, 0.70 [95% CI, 0.51-0.96]). Reduced mortality associated with hypothyroidism was seen only in those without significant comorbidities and not in those with other serious diseases. Atrial fibrillation at presentation (P = .02) and an increment of 10 pmol/L in serial free T₄ concentration during follow-up (P = .009) were independently associated with mortality. Among hyperthyroid subjects aged 40 years or older, mortality was increased during periods of thionamide treatment and after radioiodine not resulting in hypothyroidism, but not during follow-up after radioiodine-induced hypothyroidism. Independent associations of mortality with atrial fibrillation and incomplete biochemical control during treatment indicate potential causative links with poor outcome.
The Journal of Clinical Endocrinology & Metabolism, 2010
The absence of classical symptoms and signs of hyperthyroidism often results in delayed diagnosis... more The absence of classical symptoms and signs of hyperthyroidism often results in delayed diagnosis and treatment. The objective of the study was to determine the prevalence of symptoms and signs of hyperthyroidism according to patients&#39; age and gender as well as severity and type of hyperthyroidism. This was a cross-sectional study of 3049 consecutive patients with hyperthyroidism presenting to a single secondary/tertiary care clinic. Calculation of adjusted odds ratios for presence/absence of symptoms/signs of hyperthyroidism simultaneously analyzing the influence of patients&#39; age/gender, disease etiology/severity, symptom duration, and smoking. The majority of patients older than 61 yr had two or more symptoms. The lowest proportion of subjects reporting five or more symptoms was found in those older than 61 yr. Increasing age was associated with reduced adjusted odds ratio for the presence of most classical symptoms except for weight loss and shortness of breath, independent of disease severity. Those with more severe hyperthyroidism and smokers had increased odds ratios for most symptoms. Older age, higher serum free T(4) concentrations at diagnosis, male gender, and toxic nodular hyperthyroidism were independently associated with risk of atrial fibrillation. Signs of ophthalmopathy were associated with increasing age, smoking, longer symptom duration, and female gender. Classical symptoms and signs of hyperthyroidism are significantly less prevalent in older patients and more prevalent in smokers and subjects with higher free T(4) concentrations. We propose a lower threshold for performing thyroid function tests in patients older than 60 yr, especially in those presenting with atrial fibrillation, weight loss, or shortness of breath.
The Journal of Clinical Endocrinology & Metabolism, 2006
Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first inve... more Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. The design was a prospective cohort. The study was conducted at a single secondary/tertiary care clinic. One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. There were no interventions. Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH &lt; 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P &lt; 0.001, compared with TSH &lt; 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient&#39;s gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.
Human Reproduction, 2005
The fifth report of the ESHRE PGD Consortium is presented (data collection V). For the first time... more The fifth report of the ESHRE PGD Consortium is presented (data collection V). For the first time, the cycle data were collected for one calendar year (2002) in the following October, so that data collection was complete for pregnancies and babies. The data were collected using a Filemaker Pro database and divided into referrals, cycles, pregnancies and babies. There are currently 66 active centres registered with the consortium; however, the data presented here were obtained from 43 centres and included 1603 referrals, 2219 cycles, 485 pregnancies and 382 babies born. The cycle data were divided into preimplantation genetic diagnosis (PGD) for inherited disorders (including chromosome abnormalities, sexing for X-linked disease and monogenic disorders), aneuploidy screening (PGS) and the use of PGD for social sexing. Data collection V is compared with the previous cumulative data collection (I-IV), which comprised 4058 PGD/PGS cycles that reached oocyte retrieval.
European Journal of Endocrinology, 2001
The initial management of large non-functioning pituitary adenomas is surgical debulking. In some... more The initial management of large non-functioning pituitary adenomas is surgical debulking. In some cases, postoperative radiotherapy (RT) is administered in order to reduce the likelihood of tumour regrowth. Historically, there have been concerns surrounding a number of potentially significant complications of pituitary RT. Recent contributions to the literature, however, suggest that pituitary RT may be less hazardous than was originally thought. This article reviews the evidence relating to the potential side-effects of RT and weighs these risks against the clinically beneficial effects of preventing pituitary tumour regrowth.
Endocrinology, 2014
The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid... more The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity-ligation assays, we show that PBF binds specifically to p53 in thyroid cells and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroidspecific PBF overexpression (transgenic PBF mice), which had significantly increased genetic instability as indicated by fluorescent inter simple sequence repeat-PCR analysis. Consistent with this, approximately 40% of all DNA repair genes examined were repressed in transgenic PBF primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51, and Xrcc3. Our data also revealed that PBF induction resulted in up-regulation of the E2 enzyme Rad6 in murine thyrocytes and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the protooncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, in which PBF is generally overexpressed and p53 mutations are rare compared with other tumor types.
Endocrine, 2014
Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (C... more Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using nextgeneration sequencing in all primary CH cases.
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Papers by Kristien Boelaert