Publications by authors named "Ulla Feldt-Rasmussen"

254 Publications

Multiple endocrine neoplasia type 1 (MEN1) and neuroendocrine neoplasms (NENs).

Semin Cancer Biol 2021 Apr 24. Epub 2021 Apr 24.

ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark; Institute of Clinical Medicine, Faculty of Health Sciences, Copenhagen University, Denmark. Electronic address:

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.04.011DOI Listing
April 2021

Off-label treatment with Pasireotide and use of continuous glucose monitoring in late familial hyperinsulinemic hypoglycemia: a case report.

Acta Diabetol 2021 Apr 24. Epub 2021 Apr 24.

Department of Medical Endocrinology and Metabolism PE7562, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1007/s00592-021-01723-9DOI Listing
April 2021

Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.

Elife 2021 04 6;10. Epub 2021 Apr 6.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.

Methods: In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.

Results: We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).

Conclusions: We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.

Funding: The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.

Clinical Trial Number: NCT02152553.
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http://dx.doi.org/10.7554/eLife.62236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024021PMC
April 2021

Multiple endocrine neoplasia type 2: A reveiw.

Semin Cancer Biol 2021 Apr 1. Epub 2021 Apr 1.

Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark. Electronic address:

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.03.035DOI Listing
April 2021

Levothyroxine Therapy in Elderly Patients With Hypothyroidism.

Front Endocrinol (Lausanne) 2021 12;12:641560. Epub 2021 Mar 12.

Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Levothyroxine (L-T4) treatment of overt hypothyroidism can be more challenging in elderly compared to young patients. The elderly population is growing, and increasing incidence and prevalence of hypothyroidism with age are observed globally. Elderly people have more comorbidities compared to young patients, complicating correct diagnosis and management of hypothyroidism. Most importantly, cardiovascular complications compromise the usual start dosage and upward titration of L-T4 due to higher risk of decompensating cardiac ischemia and -function. It therefore takes more effort and care from the clinician, and the maintenance dose may have to be lower in order to avoid a cardiac incidence. On the other hand, L-T4 has a beneficial effect on cardiac function by increasing performance. The clinical challenge should not prevent treating with L-T4 should the patient develop e.g., cardiac ischemia. The endocrinologist is obliged to collaborate with the cardiologist on prophylactic cardiac measures by invasive cardiac surgery or medical therapy against cardiac ischemic angina. This usually allows subsequent successful treatment. Management of mild (subclinical) hypothyroidism is even more complex. Prevalent comorbidities in the elderly complicate correct diagnosis, since many concomitant morbidities can result in non-thyroidal illness, resembling mild hypothyroidism both clinically and biochemically. The diagnosis is further complicated as methods for measuring thyroid function (thyrotropin and thyroxine) vary immensely according to methodology and background population. It is thus imperative to ensure a correct diagnosis by etiology (e.g., autoimmunity) before deciding to treat. Even then, there is controversy regarding whether or not treatment of such mild forms of hypothyroidism in elderly will improve mortality, morbidity, and quality of life. This should be studied in large cohorts of patients in long-term placebo-controlled trials with clinically relevant outcomes. Other cases of hypothyroidism, e.g., medications, iodine overload or hypothalamus-pituitary-hypothyroidism, each pose specific challenges to management of hypothyroidism; these cases are also more frequent in the elderly. Finally, adherence to treatment is generally challenging. This is also the case in elderly patients, which may necessitate measuring thyroid hormones at individually tailored intervals, which is important to avoid over-treatment with increased risk of cardiac morbidity and mortality, osteoporosis, cognitive dysfunction, and muscle deficiency.
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http://dx.doi.org/10.3389/fendo.2021.641560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006441PMC
March 2021

Determining minimal important change for the thyroid-related quality of life questionnaire ThyPRO.

Endocr Connect 2021 Mar;10(3):316-324

Department of Public Health, University of Copenhagen, Copenhagen, Denmark.

Objective: ThyPRO is the standard thyroid patient-reported outcome (PRO). The change in scores that patients perceive as important remains to be ascertained. The purpose of this study was to determine values for minimal important change (MIC) for ThyPRO.

Methods: A total of 435 patients treated for benign thyroid diseases completed ThyPRO at baseline and 6 weeks following treatment initiation. At 6 weeks follow-up, patients also completed Global Rating of Change items. For each 0-100 scale, two MIC values were identified: An MIC for groups, using the receiver operating characteristic (ROC) curve method and an MIC for individual patients, using the Reliable Change Index.

Results: ROC analyses provided group-MIC estimates of 6.3-14.3 (score range 0-100). Evaluation of area under the curve (AUC) supported the robustness for 9 of 14 scales (AUC > 0.7). Reliable Change Index estimates of individual-MIC were 8.0-21.1. For all scales but two, the individual-MIC values were larger than the group-MIC values.

Conclusions: Interpretability of ThyPRO was improved by the establishment of MIC values, which was 6.3-14.3 for groups and 8.0-21.1 for individuals. Thus, estimates of which changes are clinically relevant, are now available for future studies. We recommend using MIC values found by ROC analyses to evaluate changes in groups of patients, whereas MIC values identified by a dual criterion, including the reliability of changes, should be used for individual patients, for example, to identify individual responders in clinical studies or practice.
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http://dx.doi.org/10.1530/EC-21-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052573PMC
March 2021

The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions.

Mol Cell Endocrinol 2021 04 4;525:111173. Epub 2021 Feb 4.

Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark.

The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs. The hypothalamus and the pituitary gland are in close anatomical proximity at the base of the brain and extended through the pituitary stalk to the sella turcica. The pituitary stalk allows passage of stimulatory and inhibitory hormones and other signal molecules. The target organs are placed in the periphery and function through stimulation/inhibition by the circulating pituitary hormones. The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear. The diagnosis of central hypothyroidism is complicated by itself but challenged further by concomitant affection of other hypothalamus-pituitary-hormone axes, the dysfunction of which influences the diagnosis of central hypothyroidism. Treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes also influence the function of the others by complex mechanisms involving both central and peripheral mechanisms. Clinicians managing patients with neuroendocrine disorders should become aware of the strong integrative influence from each hypothalamus-pituitary-hormone axis on the physiology and pathophysiology of central hypothyroidism. As an aid in this direction the present review summarizes and highlights the importance of the hypothalamus-pituitary-thyroid axis, pitfalls in diagnosing central hypothyroidism, diagnosing/testing central hypothyroidism in relation to panhypopituitarism, pointing at interactions of the thyroid function with other pituitary hormones, as well as local hypothalamic neurotransmitters and gut-brain hormones. Furthermore, the treatment effect of each axis on the regulation of the others is described. Finally, these complicating aspects require stringent diagnostic testing, particularly in clinical settings with lower or at least altered à priori likelihood of hypopituitarism than in former obvious clinical patient presentations.
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http://dx.doi.org/10.1016/j.mce.2021.111173DOI Listing
April 2021

Incidence and Clinical Presentation of Pheochromocytoma and Sympathetic Paraganglioma: A Population-based Study.

J Clin Endocrinol Metab 2021 Apr;106(5):e2251-e2261

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Context: Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers.

Objective: We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study.

Methods: We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data.

Results: SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare.

Conclusion: Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a "new" group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.
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http://dx.doi.org/10.1210/clinem/dgaa965DOI Listing
April 2021

Sex differences in acromegaly at diagnosis: A nationwide cohort study and meta-analysis of the literature.

Clin Endocrinol (Oxf) 2021 Apr 26;94(4):625-635. Epub 2020 Dec 26.

Department of Endocrinology, Aarhus University Hospital, Aarhus C, Denmark.

Objective: Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.

Design: A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed.

Method: Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated.

Results: The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R  = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-I was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females. In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I  = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable.

Conclusion: There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay.
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http://dx.doi.org/10.1111/cen.14392DOI Listing
April 2021

Improvement of gastrointestinal symptoms in a significant proportion of male patients with classic Fabry disease treated with agalsidase beta: A Fabry Registry analysis stratified by phenotype.

Mol Genet Metab Rep 2020 Dec 30;25:100670. Epub 2020 Oct 30.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

Background: Fabry disease is an inherited disorder of glycolipid metabolism with progressive involvement of multiple organs, including the gastrointestinal tract, in classically affected male patients. Clinical presentations in males with later-onset Fabry phenotypes are more heterogeneous and largely dependent on the level of residual α-galactosidase A activity.

Methods: We assessed agalsidase beta treatment outcomes of gastrointestinal symptoms in adult males with classic or later-onset Fabry disease. Self-reports of abdominal pain and diarrhea ('present'/'not present' since previous assessment) at last clinical visit (≥0.5 year of follow-up) were compared with treatment-baseline.

Results: Classic male patients were considerably younger at first treatment than the fewer males with later-onset phenotypes (36 vs. ~47 years) and reported gastrointestinal symptoms more frequently at baseline (abdominal pain: 56% vs. 13%; diarrhea: 57% vs. 23%). As compared with baseline, significantly fewer classic patients reported abdominal pain after a median of 4.7 years of treatment ( = 171, 56% vs. 41%,  < 0.001). Moreover, significantly fewer patients reported diarrhea after 5.5 years of follow-up ( = 169, 57% vs. 47%,  < 0.05). Among the males with later-onset phenotypes, albeit statistically non-significant, abdominal pain reports reduced after a median of 4.2 years ( = 48, 13% vs. 4%) and diarrhea reports reduced after a median of 4.4 years of treatment ( = 47, 23% vs. 13%).

Conclusions: Sustained treatment with agalsidase beta was associated with improvement in abdominal pain and diarrhea in a significant proportion of classic male Fabry patients. Males with later-onset phenotypes reported gastrointestinal symptoms much less frequently at baseline as compared with classic patients, and non-significant reductions were observed.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606866PMC
December 2020

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

J Clin Endocrinol Metab 2021 Mar;106(4):1183-1194

Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Sweden.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.

Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.

Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.

Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.
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http://dx.doi.org/10.1210/clinem/dgaa749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993578PMC
March 2021

The effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments.

Endocrine 2021 Feb 15;71(2):467-475. Epub 2020 Oct 15.

Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Purpose: Replicating the physiological cortisol secretion is key in the treatment of glucocorticoid insufficient individuals and optimization may enhance quality of life. The study investigates fatigue measured by ecological momentary assessments in patients treated with conventional hydrocortisone compared with once-daily dual-release hydrocortisone (Plenadren).

Methods: A 21-week open-label switch pilot trial included 30 patients with adrenal insufficiency due to hypopituitarism. Fatigue was assessed four times daily for 20 days using a momentary item version of the Multidimensional Fatigue Inventory on patients' usual hydrocortisone regimen. Participants switched treatment to an identical daily dose of Plenadren for 16 weeks where fatigue assessments were repeated. Change in fatigue and diurnal variation of fatigue was analyzed using mixed models for repeated measurements.

Results: In four out of five fatigue subscales fatigue was significantly reduced 0.7-1.1 points (scales ranging from 4 to 20), when treated with Plenadren compared with conventional hydrocortisone, corresponding to small effect sizes below the scale-specific minimal important changes. However, 33% of the participants completing the study (9/27) experienced reductions in fatigue above the minimal important change. On Plenadren, we found larger between-person variances and smaller within-person variances. Finally, we identified diurnal fatigue curves for both treatments.

Conclusions: The Plenadren-related reduction in fatigue was significant but not necessarily of clinical importance when looking at a group level. However, there was a large interindividual variation in treatment effect, why patients with a large benefit in quality of life should be identified. Future RCTs should be powered to detect the effect magnitudes identified here.
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http://dx.doi.org/10.1007/s12020-020-02507-xDOI Listing
February 2021

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study.

Mol Genet Metab 2020 Sep - Oct;131(1-2):219-228. Epub 2020 Aug 15.

Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.
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http://dx.doi.org/10.1016/j.ymgme.2020.07.007DOI Listing
August 2020

Globotriaosylsphingosine (lyso-Gb) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort.

J Med Genet 2020 Sep 22. Epub 2020 Sep 22.

Pediatrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Introduction: Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb) and related analogues, deacylated forms of globotriaosylceramide (Gb), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease.

Methods: We evaluated Gb, lyso-Gb and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb and analogues at (-28), (-2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb and lyso-Gb analogues at (-12) and (+14) were evaluated in urine while the analogue at (+18) was evaluated in plasma.

Results: A strong correlation between plasma and urine lyso-Gb and analogue levels was revealed. Plasma and urine lyso-Gb and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb and analogues at (-28), (-2), (+16), (+34) and the seven urinary lyso-Gb analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb and five analogues, as well as urine Gb and six lyso-Gb analogues, but not lyso-Gb and lyso-Gb at (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa.

Conclusion: Women with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.
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http://dx.doi.org/10.1136/jmedgenet-2020-107162DOI Listing
September 2020

Hashimoto's thyroiditis as a risk factor for thyroid cancer.

Curr Opin Endocrinol Diabetes Obes 2020 10;27(5):364-371

Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet.

Purpose Of Review: To summarize the recent developments in considering Hashimoto's thyroiditis as a risk factor for thyroid cancer.

Recent Findings: Modern approaches to understanding the co-occurrence of Hashimoto's thyroiditis and thyroid cancer have consistently found increased prevalence of both conditions, separately as well as of their coexistence. The inflammatory process in Hashimoto's thyroiditis is understood as a potential risk factor for thyroid cancer development. This has also provided a better understanding of the limitations in the current diagnostic and follow-up armamentarium for both conditions, resulting in international guidelines from the clinical and scientific societies. Other recent developments call for a paradigm shift in guidelines on thyroid carcinomas when lymphocytic infiltration is present, which potentially should always be considered the case at least in areas of sufficient iodine intake.

Summary: The literature of Hashimoto's thyroiditis as a risk factor for thyroid cancer is reviewed over the last year to highlight new developments in the understanding of their association and future clinical implications.
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http://dx.doi.org/10.1097/MED.0000000000000570DOI Listing
October 2020

Comment on: Adrenal insufficiency in prednisolone-treated patients with polymyalgia rheumatica or giant cell arteritis-prevalence and clinical approach: reply.

Rheumatology (Oxford) 2020 10;59(10):e78

Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Frederiksberg.

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http://dx.doi.org/10.1093/rheumatology/keaa239DOI Listing
October 2020

Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes.

Endocr Connect 2020 Aug;9(8):793-803

Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, and Faculty of Health, Institute of Clinical and Scientific Research, Copenhagen, Denmark.

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.
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http://dx.doi.org/10.1530/EC-20-0279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487185PMC
August 2020

Disease Control and Gender Predict the Socioeconomic Effects of Acromegaly: A Nationwide Cohort Study.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Endocrinology, Aarhus University Hospital, Aarhus C, Denmark.

Context: Acromegaly is an insidious disease associated with severe somatic morbidity but data on socioeconomic status are scarce.

Objective: To study the socioeconomic status in acromegaly in a population-based follow-up study.

Methods: All incident cases of acromegaly (n = 576) during the period 1977-2010 were included. For every patient, 100 persons were sampled from the general population matched for date of birth and gender (comparison cohort). Cox regression and hazard ratios (HR), conditional logistic regression and linear regression with 95% confidence intervals (CI) were used.

Outcome Measures: Retirement, social security benefit, annual income, cohabitation, separation, parenthood and educational level.

Results: The proportion of retired individuals was significantly higher in patients with acromegaly after the time of diagnosis (HR, 1.43; 95% CI, 1.26-1.62) and also during the 5-year pre-diagnostic period (HR, 1.15; 95% CI, 1.03-1.28). More individuals with acromegaly received social security benefit compared with the comparison cohort during the initial period after the time of diagnosis. Among patients who maintained a job, the annual income was similar to the comparison cohort. Compared with the background population, cohabitation was lower (HR, 0.69; 95% CI, 0.50-0.95) as was parenthood (HR, 0.56; 95% CI, 0.39-0.80), whereas neither educational level (HR, 0.61; 95% CI, 0.35-1.06) nor separation (HR, 1.13; 95% CI, 0.86-1.47) were different. Female gender and insufficient disease control were associated with a significantly worse socioeconomic status.

Conclusions: 1) Socioeconomic status is impaired in patients with acromegaly even before a diagnosis of acromegaly. 2) Females and patients without disease remission have worse outcomes. 3) Early diagnosis and effective treatment of acromegaly could be important factors in mitigating the negative impact on socioeconomic factors.
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http://dx.doi.org/10.1210/clinem/dgaa405DOI Listing
September 2020

Ecological momentary assessments (EMAs) did not improve responsiveness of patient-reported outcomes on quality of life.

J Clin Epidemiol 2020 09 7;125:138-147. Epub 2020 Jun 7.

Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, Copenhagen, Denmark. Electronic address:

Objectives: Clinical practice guidelines recommend questionnaires with short recall. We compare responsiveness of ecological momentary assessments (EMAs) and retrospective assessments of thyroid-related quality of life.

Study Design And Setting: Patients with newly diagnosed thyrotoxicosis completed retrospective Thyroid-related Patient-Reported Outcome measures (ThyPROs) with 4-week and 1-week recall, respectively, and three daily EMAs for 4 weeks at time of inclusion and again after treatment (N = 115). Magnitude of change and statistical power (F-test statistics) were compared. Two designs were applied to the same data: Design 1 mimicked the practical realities of clinical trials by comparing 4-week recall ThyPRO administered at time of inclusion with EMA initiated at time of inclusion and collected prospectively for 1 week, thus not covering the same time frame or duration. Design 2 compared assessments covering the same 4 weeks after inclusion.

Results: Design 1: the estimated change and statistical power were significantly larger for 4-week ThyPRO compared with EMAs. Design 2: retrospective assessments and EMAs had comparable change and power. Repeated 1-week ThyPRO administrations increased the statistical power.

Conclusion: Selecting the optimal time frame for evaluation proved crucial for responsiveness. EMAs did not provide higher responsiveness than retrospective measures in either design. Repeated 1-week ThyPRO administrations increased statistical power.
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http://dx.doi.org/10.1016/j.jclinepi.2020.06.006DOI Listing
September 2020

Insulin Independence in Newly Diagnosed Type 1 Diabetes Patient following Fenofibrate Treatment.

Case Rep Med 2020 14;2020:6865190. Epub 2020 May 14.

Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

A 19-year-old girl was diagnosed with type 1 diabetes and showing polydipsia and polyuria. She was double autoantibody-positive and had a diabetes-prone tissue type. She was immediately started on insulin. Fenofibrate treatment (160 mg daily) was initiated seven days after diagnosis. The need for insulin quickly declined, and she took her last dose of insulin 19 days after the first dose of fenofibrate, having regained endogenous control of blood glucose concentrations. She has now been insulin independent for one year and 9 months. Unstimulated C-peptide has increased by 51% (317 to 479 pmol/l), and IA-2 autoantibody level has decreased by 65% (49 to 17 × 10 arbitrary units). Fenofibrate is a widely used drug for reducing triglyceride and cholesterol levels. Fenofibrate reverses and prevents autoimmune diabetes in nonobese diabetic (NOD) mice by increasing the amount of the sphingolipid sulfatide in islets. Sphingolipid metabolism is otherwise abnormal in the islets at diagnosis of type 1 diabetes. In conclusion, we describe a 19-year-old patient with classical newly diagnosed type 1 diabetes, which following fenofibrate treatment has been without insulin for 21 months.
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http://dx.doi.org/10.1155/2020/6865190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245672PMC
May 2020

Fluispotter, a novel automated and wearable device for accurate volume serial dried blood spot sampling.

Bioanalysis 2020 May 3;12(10):665-681. Epub 2020 Jun 3.

Department of Clinical Biochemistry, KB3011, Rigshospitalet, Copenhagen, Denmark.

A novel automated serial dried blood spot (DBS) sampler, 'Fluispotter', was tested for its sampling performance. An LC-MS/MS method was developed for the analysis of cortisol in DBS samples serially spotted by Fluispotter. The cortisol concentrations in 148 paired DBS and plasma samples were compared across a hematocrit (HCT) range of 22-55%. The interassay accuracy and precision were <10%. Overall assay bias was negligible across the HCTs tested when analyzing the whole-spot DBS samples. The accuracy and precision of the blood volume in 10 μl DBS samples spotted by Fluispotters and micropipettes were within 3%. Deming regression and Bland-Altman analysis showed a good agreement of DBS-predicted and measured plasma cortisol. The Fluispotter performed serial sampling with high accuracy and precision of the sample blood volume.
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http://dx.doi.org/10.4155/bio-2020-0048DOI Listing
May 2020

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

Lancet Diabetes Endocrinol 2020 06;8(6):501-510

ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.

Background: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight.

Methods: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496.

Findings: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (p=0·10). Each 1 SD increase in FT concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second.

Interpretation: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy.

Funding: Netherlands Organization for Scientific Research (grant 401.16.020).
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http://dx.doi.org/10.1016/S2213-8587(20)30061-9DOI Listing
June 2020

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

Clin Endocrinol (Oxf) 2020 08 18;93(2):146-153. Epub 2020 May 18.

Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus C, Denmark.

Context: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved.

Objective: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant.

Methods: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants.

Results: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons.

Conclusions: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.
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http://dx.doi.org/10.1111/cen.14207DOI Listing
August 2020

Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review.

J Inherit Metab Dis 2020 09 12;43(5):922-933. Epub 2020 May 12.

Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer-reviewed publications and case-reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha-galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb ) and sphingosine-globotriaosylceramide (lyso-Gb ) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non-elevated lysoGb /Gb concentrations and lack of intracellular Gb accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.
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http://dx.doi.org/10.1002/jimd.12240DOI Listing
September 2020

Quality of life and psychological functioning in postmenopausal women undergoing aromatase inhibitor treatment for early breast cancer.

PLoS One 2020 26;15(3):e0230681. Epub 2020 Mar 26.

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Introduction: Aromatase inhibitors (AIs) dramatically increased breast cancer (BC) survival, leading to enhanced attention to their long-term consequences on psychological functioning. Conflicting data has been examined regarding the association between AIs administration and the clinical psychological features in BC survivors (BCSs).

Purpose: As psychological symptoms often occur in such chronic diseases, our study aimed at exploring anxious and depressive symptoms and the perceived quality of life (QoL) in BCSs assessed for osteoporosis.

Methods: The total sample consisted of a clinical sample of 51 outpatient postmenopausal women, diagnosed with BC, and a control group composed of 51 healthy postmenopausal women. All recruited participants were evaluated through the clinical gold standard interview and completed the following self-rating scales: the Hamilton Anxiety Rating Scale, Beck Depression Inventory II edition, and 36-Item Short Form Health Survey, which were administered at baseline and after 6 months in BCSs in AIs treatment, compared with controls. Moreover, all participants were assessed for vitamin D status, bone mineral density (BMD) and subclinical vertebral fractures. Data regarding age, age at menopause, body mass index (BMI), smoking habits and alcohol consumption was collected.

Results: BCSs (n = 51) showed higher anxious and depressive symptoms, and lower perceived QoL vs. controls (n = 51) (p<0.05 for all). After 6 months of treatment with AIs, BCSs showed significant reduction of anxious and depressive symptoms and a significantly higher perceived QoL for both physical and mental components, vs. controls.

Conclusions: The improvement of clinical psychological features and perceived QoL was associated with AIs treatment in women being treated with, for early breast cancer. Further studies are needed to obtain a deeper comprehension of the correlation between clinical psychological and physical features in BCSs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230681PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098625PMC
June 2020

Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis.

ESC Heart Fail 2020 06 26;7(3):825-834. Epub 2020 Feb 26.

Unidad de Dialisis, IIS-Fundación Jiménez Díaz, UAM, IRSIN, REDINREN, Madrid, Spain.

Aims: Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.

Methods And Results: Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, P  <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, P  = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m /year, P  = 0.80).

Conclusions: Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.
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http://dx.doi.org/10.1002/ehf2.12647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261571PMC
June 2020

Adrenal insufficiency in prednisolone-treated patients with polymyalgia rheumatica or giant cell arteritis-prevalence and clinical approach.

Rheumatology (Oxford) 2020 10;59(10):2764-2773

Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Bispebjerg and Frederiksberg, Frederiksberg, Denmark.

Objectives: Glucocorticoid treatment is fundamental in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but carries a risk of glucocorticoid-induced adrenal insufficiency. Adrenal insufficiency can cause reluctance to stop glucocorticoid treatment after disease remission as symptoms can resemble PMR/GCA flare. We aimed to determine the prevalence of adrenal insufficiency in prednisolone-treated patients with PMR/GCA.

Methods: We included 47 patients with PMR (n = 37), GCA (n = 1) or both (n = 9), treated with prednisolone for ≥5.4 months, current dose 2.5-10 mg/day. Adrenal function was evaluated using a corticotropin (Synacthen®) stimulation test following 48 h prednisolone pause. Two years' clinical follow-up data are provided.

Results: Seven patients (15%) had adrenal insufficiency, 4 (11%) of the 37 patients with PMR alone, and 3 (30%) of the 10 patients with GCA. Corticotropin-stimulated P-cortisol was significantly associated with current prednisolone dose, mean daily dose the last 3 and 6 months before testing, and basal P-cortisol, but not with total dose or treatment duration. Adrenal insufficiency occurred with all current prednisolone doses (2.5-10 mg/day). Five (71%) of the glucocorticoid-insufficient patients could discontinue prednisolone treatment; two of them recovered glucocorticoid function, whereas three still needed hydrocortisone replacement 2 years later. Two patients experienced in total four acute hospital admissions with symptoms of adrenal crises.

Conclusion: Glucocorticoid-induced adrenal insufficiency occurred in 15% of patients with PMR/GCA. Mean prednisolone dose the last 3 months and basal P-cortisol were the best and simplest predictors of adrenal function. Most of the glucocorticoid-insufficient patients could discontinue prednisolone with appropriate treatment for adrenal insufficiency.
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http://dx.doi.org/10.1093/rheumatology/keaa011DOI Listing
October 2020

Shorter Recall Period for the Thyroid-Related Patient-Reported Outcome Measure ThyPRO Did Not Change the Accuracy as Evaluated by Repeated Momentary Measurements.

Thyroid 2020 02;30(2):185-191

Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The thyroid-related patient-reported outcome measure ThyPRO has become the gold standard for measuring thyroid-related quality of life and uses a 4-week recall period. The impact of the length of recall is unresolved. To minimize recall bias, the US Food and Drug Administration has argued in favor of short recall periods or measures describing current states. We investigated whether a 1-week recall version of ThyPRO was less prone to recall bias than the original ThyPRO, using averaged momentary ThyPRO measurements as the hypothesized true mean of patients' symptoms. Patients newly diagnosed with thyrotoxicosis were included ( = 122). During a 28-day study period, participants answered momentary questions three times daily via a smartphone, weekly retrospective surveys with a 1-week recall period, and the original survey with a 4-week recall period on day 28. Twelve ThyPRO items from four multi-item scales were used. Mean momentary ratings for each scale were compared with recall ratings of 1- and 4-week periods, respectively. The mean momentary ratings were highly correlated with retrospective ratings and remained rather constant when altering the reporting period from four weeks to one week. We found consistently lower scores (i.e., better thyroid-related quality of life) on momentary ratings compared with retrospective ratings. The mean differences between momentary ratings and retrospective ratings were similar for both recall periods. The original 4-week ThyPRO accurately summarized the mean of all 1-week ThyPROs. Shortening the recall period of ThyPRO from four weeks to one week was not associated with less recall bias within this subset of items. Nor did 1-week recall seem to compromise the accuracy of ThyPRO. Thus, either version of ThyPRO can be used in future studies.
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http://dx.doi.org/10.1089/thy.2019.0380DOI Listing
February 2020

Semen quality in hypogonadal acromegalic patients.

Pituitary 2020 Apr;23(2):160-166

Department of Growth and Reproduction 5064, Rigshospitalet, Faculty of Health Science, University of Copenhagen, 5064, Copenhagen, Denmark.

Objective: Growth hormone (GH) activity might be implicated in male reproductive function. One previous study has suggested significantly reduced semen quality in untreated acromegalic patients due to both reduced sperm counts and sperm motility.

Design And Methods: A retrospective study comprising ten uncontrolled hypogonadal acromegalic patients (median age 29 years) who delivered semen for cryopreservation before initiation of testosterone therapy. Semen variables and hormone concentrations were compared to those of ten non-acromegalic hypogonadal men with pituitary disease (age 31 years) and those of young healthy men.

Results: Acromegalic patients vs. non-acromegalic patients had a higher percentage of progressive motile spermatozoa (62 vs. 47%, p = 0.04). Eight of ten acromegalic patients and 82% of controls had total sperm counts above 39 million and progressive motile spermatozoa above 32% (p = 0.55), corresponding to the WHO 2010 reference levels for expected normal fertility for these variables. Non-acromegalic patients vs. healthy controls had reduced percentage of progressive motile spermatozoa (47 vs. 57%, p = 0.02) and only five of ten patients had semen quality above the WHO reference level, which was significantly lower than observed in healthy controls (p = 0.022). Total sperm counts were similar between both patient groups and controls. There were no differences in reproductive hormone levels between acromegalic patients vs. non-acromegalic patients (p-values between 0.10 and 0.61). Compared to healthy controls both patient groups had severely reduced serum testosterone, calculated free testosterone.

Conclusions: Despite severe hypoandrogenism acromegalic patients had semen quality similar to healthy controls based on determination of the number of progressively motile spermatozoa. By contrast non-acromegalic pituitary patients had reduced sperm motility. Our data do not support reduced semen quality in acromegaly.
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http://dx.doi.org/10.1007/s11102-019-01018-xDOI Listing
April 2020

Significant hearing loss in Fabry disease: Study of the Danish nationwide cohort prior to treatment.

PLoS One 2019 6;14(12):e0225071. Epub 2019 Dec 6.

Department of Medical Endocrinology, Copenhagen University Hospital (Rigshospitalet), Copenhagen University, Copenhagen, Denmark.

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide resulting in multi-organ dysfunction e.g. cerebral, cardiac, renal and audiologic complications. The audiologic involvement in FD has often been neglected; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life.

Objectives: To investigate baseline hearing status of the Danish Fabry cohort prior to treatment, compared to sex- and age-expected hearing levels and correlating hearing to renal and cerebral findings.

Material And Methods: Retrospective study of baseline hearing status of the Danish Fabry cohort (n = 83, 9-72 years). Air conduction and speech discrimination scores were assessed at 6 frequencies between 0.25-8 kHz bilaterally. Data were collected between 2001-2014 and compiled in STATA using multilinear mixed modelling for statistical evaluation.

Results: Hearing thresholds at all frequencies deviated from the expected thresholds of an otologically normal cohort (p<0.001) and ranged 0.5 to 1.5 standard deviations below expected values. In total 29 males and 54 females were included. Hearing loss was more pronounced in the higher frequencies. There was a trend of association between hearing loss and measured glomerular filtration rate (mGFR) (p = 0.084). No association was present between hearing loss and albuminuria (p = 0.90), Fabry related cerebral abnormalities (p = 0.84) and cardiac left ventricular mass index, (LVMi) (p = 0.67) independent of sex. Hearing thresholds were poorer for men compared to women (p = 0.001). Sex differences were present at 0.25, 4 and 8 kHz.

Conclusion: Our findings demonstrated significant hearing loss in Danish FD patients before treatment initiation, being more profound than in otologically healthy individuals at all frequencies. Additionally, we observed no association between hearing loss and LVMi, albuminuria or FD cerebral abnormalities, with a trend of association to mGFR.

Synopsis: Patients with Fabrys disease have hearing loss of all frequencies and most prominently at high frequencies (4-8 kHz), with no association between the hearing loss and cerebral abnormalities, and cardiac mass but with a trend of association to measured glomerular filtration rate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897399PMC
March 2020