Publications by authors named "Philippe Caron"

150 Publications

New therapies for patients with multiple endocrine neoplasia type 1.

Ann Endocrinol (Paris) 2021 Apr 8. Epub 2021 Apr 8.

France. Electronic address:

In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the Multiple Endocrine Neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment. Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement. The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years. As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery. As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients. Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients. Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.
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http://dx.doi.org/10.1016/j.ando.2021.03.005DOI Listing
April 2021

What Is the Quality of Life in Patients Treated with Levothyroxine for Hypothyroidism and How Are We Measuring It? A Critical, Narrative Review.

J Clin Med 2021 Mar 30;10(7). Epub 2021 Mar 30.

Service d'Endocrinologie, Maladies Métaboliques et Nutrition, Pôle Cardio-Vasculaire et Métabolique, Hôpital Larrey, CHU de Toulouse, 31059 Toulouse, France.

Thyroid hormone replacement therapy (THRT, generally using oral levothyroxine (LT4)) is a safe, effective means of treating hypothyroidism. However, a proportion of LT4-treated patients with biochemically normal thyroid function tests complain of persistent symptoms that impact their health-related quality of life (QoL). The objectives of this critical, narrative review of the literature were to identify studies of QoL in LT4-treated patients with hypothyroidism, examine the instruments used to measure QoL, determine whether normal QoL is restored by THRT, and identify factors associated with QoL. The PubMed database was searched from 1 January 2000 to 31 December 2020. A total of 809 publications were screened, 129 full-text articles were retrieved, and 58 were analyzed. The studies of overt hypothyroidism evidenced an improvement in psychological and emotional well-being after three to six months of THRT with LT4, although contrasting results were found for patients with subclinical hypothyroidism. Combination treatment with LT4 and liothyronine was not generally associated with better QoL. In hypothyroidism, QoL appears to be influenced by a number of physiological, behavioral, cognitive and/or lifestyle factors that are not strictly related to thyroid hormone levels.
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http://dx.doi.org/10.3390/jcm10071386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037475PMC
March 2021

Thyroiditis and SARS-CoV-2 pandemic: a review.

Authors:
Philippe Caron

Endocrine 2021 Mar 27. Epub 2021 Mar 27.

Department of Endocrinology and Metabolic diseases, Cardiovascular and Metabolic Unit CHU-Larrey, Toulouse, France.

The world is dealing with the Covid-19 pandemic due to the coronavirus SARS-CoV-2. Amongst the extra-pulmonary manifestations presented by Covid-19 patients, thyroiditis form part of the spectrum of visceral involvement linked to SARS-CoV-2. In this review, we will describe the various documented clinical forms of thyroiditis (inflammatory thyroiditis, subacute or de Quervain's thyroiditis, chronic lymphocytic thyroiditis or Hashimoto's disease, painless (silent) postpartum thyroiditis) to facilitate their diagnosis in more or less symptomatic Covid-19 patients and to provide guidance for patient treatment.
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http://dx.doi.org/10.1007/s12020-021-02689-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000691PMC
March 2021

Treatment of moderate to severe orbitopathy: Current modalities and perspectives.

Ann Endocrinol (Paris) 2021 Mar 4. Epub 2021 Mar 4.

Service d'endocrinologie et maladies métaboliques, pôle cardiovasculaire et métabolique, CHU Larrey, 24, chemin de Pouvourville, 31400 Toulouse, France.

Graves' orbitopathy (GO) is the primary cause of exophthalmos in adults. It appears in 30 to 50% of patients with Graves' disease. About 5% are moderate-to-severe cases that might be see-threatening or lead to long term disabling sequelae. Recommendations have been established in 2016 by the European thyroid association (ETA) and the European group on Grave's orbitopathy (EUGOGO), suggesting a wide use of corticosteroids in moderate to severe forms. However, disappointing results have been reported in 20 to 30% of cases. Improved understanding of pathophysiological mechanisms has allowed the use of non-specific immunomodulatory agents, currently under evaluation, and which place in the therapeutic strategy remains to be determined. Very recently, new promising therapeutic advances have emerged with the identification of new therapeutic targets, such as the TSH receptor and IGF-1 receptor complex.
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http://dx.doi.org/10.1016/j.ando.2021.02.001DOI Listing
March 2021

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study.

Endocrine 2021 Jan 28;71(1):158-167. Epub 2020 Sep 28.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, 94275, Le Kremlin-Bicêtre, France.

Objective: After surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG).

Methods: We retrospectively analysed French data from ACROSTUDY.

Results: 167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG's injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same.

Conclusions: The medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.
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http://dx.doi.org/10.1007/s12020-020-02501-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835180PMC
January 2021

Thyroid disorders and SARS-CoV-2 infection: From pathophysiological mechanism to patient management.

Authors:
Philippe Caron

Ann Endocrinol (Paris) 2020 Oct 18;81(5):507-510. Epub 2020 Sep 18.

Service d'endocrinologie et maladies métaboliques, pôle cardiovasculaire et métabolique, CHU Larrey, 24, chemin de Pouvourville, TSA 30030, 31059 Toulouse cedex, France. Electronic address:

The World Health Organization (WHO) declared the COVID-19 epidemic to be a global pandemic in March 2020. COVID-19 is an infection caused by SARS-CoV-2, a coronavirus that utilizes the angiotensin-2 converting enzyme to penetrate thyroid and pituitary cells, and may result in a "cytokine storm". Based on the pathophysiological involvement of the pituitary-thyroid axis, the current review discusses the diagnosis of abnormal thyroid function test, and the management of patients presenting with thyrotoxicosis, thyroid-associated orbitopathy and hypothyroidism in the context of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.ando.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498405PMC
October 2020

Assessment of oro-dental manifestations in a series of acromegalic patients, the AcroDent study.

Endocr Connect 2020 Aug;9(8):824-833

CHU Clermont-Ferrand, Service d'Odontologie, Clermont-Ferrand, France.

Objective: The dental and periodontal impact of GH/IGF-1 hypersecretion has been poorly investigated until now. Our aim is to precisely describe the oro-dental state of acromegalic patients and to study the impact of GH/IGF-1 hypersecretion on patients' reported oral health-related quality of life (OHRQoL).

Methods: After collecting characteristics of their disease, acromegalic patients answered the GOHAI questionnaire assessing their OHRQoL, the AcroQoL questionnaire and then benefited from a complete stomatological and radiological examination (orthopantomogram systematically, retro-alveolar radiography or Cone Beam CT if necessary).

Results: In total, 29 patients aged 59.1 ± 16.0 years were included. The average DMFT index (sum of Decayed, Missing and Filled Teeth per patient) was 19.0 ± 7.8. 16/29 patients had a gingivitis and 18/29 a mild to moderate chronic periodontitis, but no case of severe chronic periodontitis was found, probably because the frequency of a protective thick gingival biotype was increased (9/29). No case of generalized gingival hypertrophy or diffuse hypercementosis was observed. According to the Add-GOHAI score, only 8/26 patients had a satisfactory OHRQoL. This parameter was correlated to the acromegaly-specific quality of life according to the AcroQoL score. Interestingly, 11/29 patients had bulky oral bony outgrowths (OBO), such as large maxillary or mandibular tori and multiple vestibular exostosis.

Conclusions: The unsatisfactory OHRQoL reported by acromegalic patients contrasts with a rather good objective oro-dental state and annual oral examination seems relevant in this population. Finally, we report that huge OBO could be helpful signposts for the diagnosis of acromegaly.
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http://dx.doi.org/10.1530/EC-20-0176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487182PMC
August 2020

First-generation somatostatin receptor ligands and pregnancy: lesson from women with acromegaly.

Endocrine 2020 11 30;70(2):396-403. Epub 2020 Jul 30.

Department of Endocrinology and Metabolic Diseases, CHU Larrey, 24 chemin de Pouvourville, TSA 30030, 31059, Toulouse Cedex, France.

Introduction: Few data are available on the risks of first-generation somatostatin receptor ligands (SRLs) during pregnancy in women treated for acromegaly. Current recommendations suggest the withdrawal of treatment at diagnosis of pregnancy. The aims of this literature review were to evaluate the teratogenic effects and the potential impact of SRLs on maternal and fetal outcomes by comparing acromegalic patients treated or not during pregnancy.

Patients And Methods: This study concerns 141 pregnancies in 127 women with acromegaly: 67 pregnancies in 62 women treated with SRLs during pregnancy and 74 pregnancies in 65 women not medically treated during pregnancy. A second analysis was then realized comparing women treated during 1st trimester only (36 pregnancies) and women treated longer (20 pregnancies).

Results: One malformation (ureteral stenosis) was reported in a newborn of a woman treated with SRL during pregnancy. No difference was found concerning maternal outcomes (gestational diabetes, hypertension, headaches, and delivery mode) and fetal outcomes (birth term, height, and weight). These results were also confirmed for the second analysis.

Conclusions: This review of the literature did report one malformation without being able to prove a specific link with the first-generation SRL treatment. No significant impact on maternal and fetal outcomes is related to first-generation SRL treatment in women with acromegaly. The number of pregnancies is still low and more data are necessary to conclude on the total safety of this treatment during gestation. In the meantime, based on the nonthreatening data from this review of literature, SRL treatment can be continued and/or reintroduced during pregnancy if necessary (mainly for persistent headaches) in women with acromegaly.
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http://dx.doi.org/10.1007/s12020-020-02430-1DOI Listing
November 2020

The Somatotropic Axis in the Sleep Apnea-Obesity Comorbid Duo.

Front Endocrinol (Lausanne) 2020 12;11:376. Epub 2020 Jun 12.

Department of Endocrinology and Metabolic diseases, Pôle Cardiovascular and Metabolic, Larrey University Hospital, Toulouse, France.

Growth hormone (GH) stimulates the production of insulin-like growth factor 1 (IGF-1) in most tissues and together GH and IGF-1 profoundly impact adipose tissue deposition, glucose metabolism and cardiovascular function. A low serum IGF-I level has been reported as being associated with obstructive sleep apnea (OSA) and might be one of the mechanisms underlying cardio-metabolic risk in OSA patients. In a multicenter national study, 817 patients consulting for suspicion of OSA (OSA confirmed for 567 patients) underwent serum IGF-1 measurements. We analyzed the association between an IGF-1 level below the median value of the population and variables related to cardio-metabolic risk: body mass index (BMI) and waist circumference, apnea hypopnea index (AHI), cholesterol and triglycerides (expressed as median and divided into quartiles for continuous variables). After adjustment for age and gender, low IGF-1 levels were associated with increased BMI and AHI (Odds ratios (OR) = 2.83; < 0.0001 and OR = 3.03, < 0.0001 for Quartile 4 vs. Quartile1, respectively), with elevated cholesterol levels (OR = 1.36, = 0.0444), and elevated triglyceride levels (OR = 1.36; = 0.0008). Both adiposity and sleep apnea synergistically predict low levels of IGF-1 and thus could together contribute toward cardio-metabolic risk. Further work are needed to confirm whether IGF-1 levels allow grading severity and predicting response to treatments to aim at a personalized medicine for patients suffering from OSA.
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http://dx.doi.org/10.3389/fendo.2020.00376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325876PMC
June 2020

Integrated multidisciplinary approach to hidradenitis suppurativa in clinical practice,.

Int J Womens Dermatol 2020 Jun 22;6(3):164-168. Epub 2020 Feb 22.

Department of Dermatology, Paul Sabatier University and Larrey Hospital, Toulouse, France.

Background: The European hidradenitis suppurativa (HS) guidelines recommend a multidisciplinary approach for patients with HS and management of comorbidities.

Objective: We aimed to describe the organization of a multidisciplinary HS program and characterize the patient population.

Methods: We conducted a retrospective study of patients with HS undergoing prospectively defined multidisciplinary work-up including examinations by a dermatologist, plastic surgeon, smoking specialist, and nutritionist in our outpatient unit between October 2015 and January 2017.

Results: The study included 49 patients with a sex ratio of 1:1. A total of 73.4% of patients were smokers, 20.4% were overweight, 48.9% were obese, and 30.6% had symptoms of depression. The mean Sartorius score was 30.4 (±17.6). The outcome of plastic surgery consultation was as follows: 16 patients had operations, 5 were excluded based on medical history, 9 refused surgery, and 16 remained undecided. The refusal rates for consulting with the smoking cessation and nutrition specialists were 55.8% and 69.5%, respectively. Twelve patients received antibiotics, 9 received biologics, 9 underwent medico-surgical treatment, 9 underwent surgery, and 10 were lost to follow-up. The mean visual analogue scale score for satisfaction was 8.3 (±1.6; n = 28).

Conclusion: An integrated multidisciplinary care model for HS is associated with high patient satisfaction. Adherence to the proposed comorbidity management was higher in female patients and related to empathetic interactions with physicians.
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http://dx.doi.org/10.1016/j.ijwd.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330447PMC
June 2020

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma.

Eur J Endocrinol 2020 Aug;183(2):221-231

Assistance Publique Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Context: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design: This was a multicenter (France and Belgium) retrospective study.

Patients: Eighteen patients treated with antipsychotics were included.

Results: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusions: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.
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http://dx.doi.org/10.1530/EJE-20-0125DOI Listing
August 2020

Management of thyroid dysfunctions in the elderly. French Endocrine Society consensus 2019 guidelines. Short version.

Ann Endocrinol (Paris) 2020 10 21;81(5):511-515. Epub 2020 May 21.

Service d'endocrinologie et maladies métaboliques, CHU de Larrey, 31059 Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.ando.2020.05.002DOI Listing
October 2020

New variant (Val597Ile) in transmembrane region of the TSH receptor with human chorionic gonadotropin hypersensitivity in familial gestational hyperthyroidism.

Clin Endocrinol (Oxf) 2020 09 16;93(3):339-345. Epub 2020 Jun 16.

Biochemistry and Genetic Laboratory, Federative Institute of Biology, CHU Toulouse, Toulouse, France.

Objectives: Only two mutations at the lysine 183 amino acid in the extracellular N-terminal domain of human TSH receptor (hTSHR) have been associated with hypersensitivity to hCG and familial gestational hyperthyroidism.

Design: Describe a new variant of the TSHR gene with hCG hypersensitivity found in two women of the same family diagnosed with gestational hyperthyroidism.

Patients: A 38-year-old woman was seen during the first trimester of her second pregnancy for thyrotoxicosis with increased fT3 and fT4 concentrations and low TSH levels without anti-TSH receptor antibody. Thyrotoxicosis improved spontaneously during the 2nd trimester and persisted at the 3rd trimester. Similar clinical symptoms (weight loss, nausea, vomiting) were also reported during the first trimester of her first pregnancy and the first pregnancy of her mother.

Results: DNA sequencing of the hTSHR gene of this woman and her mother identifies a heterozygous variant changing valine to isoleucine residue at codon 597 in the transmembrane domain (TMD) of this receptor. In vitro functional studies of this variant showed increased constitutive activity in regard to the basal level of cAMP and IP3 production and to the low cell-surface expression, while response to TSH was reduced compared to that of the wild-type receptor. The Val597Ile variant presented a dose-dependent increase in cAMP response to hGC and human luteinizing hormone (hLH). Simulation of the protein dynamics showed a high structural impact of the Val597Ile variant on helices 3 (TMH3) and 5 (TMH5) of the transmembrane domain participating to constitutive activity and hCG sensitivity.

Conclusion: We describe a new variant in the transmembrane region of the hTSHR gene with increased constitutive activity and hCG hypersensitivity in familial gestational hyperthyroidism.
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http://dx.doi.org/10.1111/cen.14215DOI Listing
September 2020

Efficacy of rituximab in patients with Graves' orbitopathy: a retrospective multicenter nationwide study.

Graefes Arch Clin Exp Ophthalmol 2020 Sep 13;258(9):2013-2021. Epub 2020 May 13.

Department of Ophthalmology, Hotel Dieu, CHU Nantes, 44093, Nantes Cedex 1, France.

Purpose: The clinical utility of rituximab (RTX) in Graves' orbitopathy (GO) treatment remains controversial since the discrepant results from 2 prospective randomized studies (Stan M et al. J Clin Endocrinol Metab 2015; Salvi M et al. J Clin Endocrinol Metab 2015). The aim of this study was to assess in real life the characteristics and the clinical outcomes of patients with GO treated with RTX in cases of corticosteroid resistance or corticosteroid dependence.

Methods: Multicenter French retrospective study including patients with moderate-to-severe GO requiring second-line treatment with RTX. Patients were classified according to three main baseline characteristics: clinical inflammation (CAS ≥ 3), oculomotor limitation, and visual dysfunction. Patients were considered as responders if, at 24 weeks (week 24), at least 1 of these 3 parameters improved with no worsening elsewhere.

Results: Forty patients were included (65% smokers, 38% dysthyroidism). Thirty-two patients were treated with RTX alone (one patient excluded owing to side effects): 64.5% had favorable responses at week 24 and significant reduction in baseline CAS (3.29 ± 1.6) at 12 weeks (1.93 ± 1.1; P < 0.001) and at week 24 (1.59 ± 1.1; P < 0.001); reduction in anti-TSH receptor antibodies at week 24 (P < 0.01); and significant improvement of visual acuity (P = 0.04) and ocular hypertonia (P = 0.04) at week 12, but no improvement in oculomotor dysfunction. Eight patients needed emergency treatment with concomitant RTX and orbital decompression, with favorable outcome for 5 patients. Predictive factors for a poor response to RTX were low baseline CAS, smoker, and baseline ocular hypertonia. All patients reported good tolerance except one serious side effect (a cytokine release syndrome).

Conclusions: The efficiency results of RTX in reducing CAS in this cohort are just between those of Stan and Salvi. This could be explained by our delay before treatment initiation, quicker than Stan but longer than Salvi. RTX appears to be effective as a second-line treatment for the inflammatory component of GO, especially if the disease is highly active and recent.
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http://dx.doi.org/10.1007/s00417-020-04651-6DOI Listing
September 2020

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

Clin Endocrinol (Oxf) 2020 09 14;93(3):248-260. Epub 2020 May 14.

Department of Endocrinology, Larrey Hospital, CardioMet Institute, University Hospital Centre of Toulouse, Toulouse, France.

Objective: Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.

Design And Patients: This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.

Results: Hypercalcaemia was diagnosed at a median age of 53 years [IQR: 38-61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63-2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1-7.1], and the median 24-hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9-4.0]. Osteoporosis (dual X-ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established.

Conclusion: This large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.
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http://dx.doi.org/10.1111/cen.14211DOI Listing
September 2020

Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.

Pituitary 2020 Apr;23(2):171-181

Department of Endocrinology and Metabolic Diseases, CHU Larrey, Toulouse, France.

Purpose: PRIMARYS (NCT00690898) was a 48-week, open-label, phase 3b study, evaluating treatment with the somatostatin receptor ligand lanreotide autogel (stable dose: 120 mg/28 days) in treatment-naïve patients with growth hormone (GH)-secreting pituitary macroadenoma. This post hoc analysis aimed to evaluate factors predictive of long-term responses.

Methods: Potential predictive factors evaluated were: sex, age, and body mass index at baseline; and GH, insulin-like growth factor-1 (IGF-1), and tumor volume (TV) at baseline and week 12, using univariate regression analyses. Treatment responses were defined as hormonal control (GH ≤ 2.5 µg/L and age- and sex-normalized IGF-1), tight hormonal control (GH < 1.0 µg/L and normalized IGF-1), or ≥ 20% TV reduction (TVR). Receiver-operating-characteristic (ROC) curves were constructed using predictive factors significant in univariate analyses. Cut-off values for predicting treatment responses at 12 months were derived by maximizing the Youden index (J).

Results: At baseline, older age, female sex, and lower IGF-1 levels were associated with an increased probability of achieving long-term hormonal control. ROC area-under-the curve (AUC) values for hormonal control were high for week-12 GH and IGF-1 levels (0.87 and 0.93, respectively); associated cut-off values were 1.19 μg/L and 110% of the upper limit of normal (ULN), respectively. Results were similar for tight hormonal control (AUC values: 0.92 [GH] and 0.87 [IGF-1]; cut-off values: 1.11 μg/L and 125% ULN, respectively). AUC and J values associated with TVR were low.

Conclusions: The use of predictive factors at baseline and week 12 of treatment could inform clinical expectations of the long-term efficacy of lanreotide autogel.
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http://dx.doi.org/10.1007/s11102-019-01020-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066297PMC
April 2020

Is MRI follow-up relevant in patients with GH-secreting pituitary adenomas primarily treated and responsive to long-acting somatostatin analogues (SMSa)?

Eur J Endocrinol 2020 Jan;182(1):123-130

Department of Endocrinology and Metabolic Diseases, CHU Larrey, Toulouse, France.

Objective: Primary SMSa treatment can be associated with hormonal control and tumor shrinkage in patients with GH-secreting pituitary adenomas. The aim of this study was to evaluate whether regular MRI follow-up was necessary in patients with acromegaly-treated and responsive to first-generation long-acting SMSa.

Patients And Methods: In this retrospective monocentric study we included patients with GH/IGF-1 hypersecretion and pituitary adenomas with normal visual field, primarily treated with first-generation long-acting SMSa between 1995 and 2015 and regularly monitored (clinical evaluation, GH/IGF-1 levels and pituitary MRI) for at least 3 years.

Results: We included 83 patients (32 men and 51 women, mean age at diagnosis 50 ± 12 years) with mean GH = 19.3 ± 25.6 ng/mL, IGF-1 = 284 ± 110% ULN and pituitary adenoma height = 12.9 ± 4.7 mm. Mean follow-up was 8.9 ± 4.9 years in 36 controlled patients and 2.0 ± 1.6 years in 47 partial responders to SMSa alone. No significant increase in pituitary adenoma height was observed. Pituitary adenoma height decreased significantly in controlled patients (diagnosis: 11.9 ± 4.8 mm, SMSa: 9.6 ± 3.3 mm, P < 0.001), and in partially responders (diagnosis: 13.6 ± 4.5 mm, SMSa: 11.5 ± 4.5 mm, P < 0.001).

Conclusion: During SMSa treatment, no significant increase in GH-secreting adenoma size was observed. Primary SMSa treatment was associated with a significantly decrease in adenoma height in our population. Our cohort data suggest that regular MRI follow-up does not seem relevant in patients with acromegaly who are responsive to SMSa treatment.
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http://dx.doi.org/10.1530/EJE-19-0681DOI Listing
January 2020

Letter to the Editor: "Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy".

J Clin Endocrinol Metab 2020 02;105(2)

Department of Endocrinology, Diabetes and Nutrition. University of Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1210/clinem/dgz105DOI Listing
February 2020

Effect of orbital radiotherapy on the outcome of surgical orbital decompression for thyroid-associated orbitopathy (TAO): a retrospective study in 136 patients.

Endocrine 2020 03 23;67(3):605-612. Epub 2019 Oct 23.

Endocrinology and Metabolic Diseases Department, CHU Larrey, 24 Chemin de Pouvourville, Toulouse, France.

Purpose: In patients with moderate to severe thyroid-associated orbitopathy (TAO), orbital radiation therapy (ORT) can prevent disease progression. In the sequelae stage, orbital decompression surgery can be useful in case of functional discomfort. The aim of this study was to evaluate the effect of orbital ORT on the outcomes of decompression surgery.

Methods: In this retrospective study, we included 136 patients who had had bilateral orbital decompression between 1995 and 2016. Before surgery, 38 patients received Radiation Therapy (RT+) while 98 did not (RT-). All RT+ patients and 20 RT- patients had systemic corticosteroid treatment. In both groups surgical outcome was evaluated by exophthalmos reduction (mm), palpebral fissure (mm), distance between the lid margin and the corneo-scleral limbus (mm), existence of conjunctival hyperemia and diplopia.

Results: In both RT+ and RT- groups, surgery improved the proptosis, significantly greater in RT+(3.66 ± 1.79 mm) than in RT- group (2.85 ± 1.80 mm) (p < 0.019). No significant differences were noted in the palpebral fissure, the distance from the lid margin to the corneo-scleral limbus. After surgery, only one patient (5%) in the RT+ group presented with new-onset diplopia, whereas in the RT- group there were 14 (36%) patients (p < 0.007). After orbital decompression, the number of conjunctival hyperemia decreased by 6 (21%) in the RT+ group versus 21 (60%) in the RT- group (p < 0.006).

Conclusion: Orbital radiotherapy during the inflammatory phase enhances the outcomes after orbital decompression in TAO. After surgery we observed a greater improvement in proptosis and in diplopia for RT+ versus RT- patients.
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http://dx.doi.org/10.1007/s12020-019-02113-6DOI Listing
March 2020

Weight-loss with activation of brown fat: Suspect pheochromocytoma.

Ann Endocrinol (Paris) 2019 Nov 26;80(5-6):314-318. Epub 2019 Jul 26.

Service d'endocrinologie et maladies métaboliques, hôpital Larrey, 24, chemin de Pouvourville, 31059 Toulouse cedex 9, France; Institut Cardiomet, hôpital Rangueil, 1, avenue du Professeur-Jean-Poulhès, 31400 Toulouse, France. Electronic address:

Introduction: Excess catecholamine stimulates heat production in brown adipose tissue (BAT). Activation of BAT can be detected in patients presenting pheochromocytoma.

Case Study: A 58-year-old female patient sought medical advice due to 13 kg weight loss over 2 years accompanied by sweating and high blood pressure. Thoracic-abdominal-pelvic CT-scan revealed a solid 40 mm mass in the left adrenal compartment with peri-adrenal nodules and a solid 80 mm mass at the lower end of the right kidney. FDG-PET scan exhibited intense uptake in the supraclavicular, intercostal, mediastinal, peri-renal, mesenteric, iliac and inguinal spaces. Renal tumor with locoregional infiltration and remote metastases was initially considered. Diagnosis of pheochromocytoma was subsequently confirmed by a 10-fold increase in urinary catecholamine, metanephrine and normetanephrine levels. Left adrenalectomy confirmed the diagnosis of pheochromocytoma, with 3 lymph-node metastases in the adjacent adipose tissue surrounded by brown fat. The patient was clinically asymptomatic with normal blood pressure at 3 months post-surgery. A weight gain of 6 kg was recorded, with normalisation of catecholamines/metanephrine/normetanephrine levels. Bilateral peri-renal infiltration (including the right renal mass) disappeared on CT-scan, and TEP-18-FDG no longer showed hypermetabolism. Recurrent mediastinal metastases were diagnosed 6 months after surgery.

Conclusion: Brown fat activation may mislead diagnosis of pheochromocytoma, suggesting multi-metastatic extra-adrenal tumor, if clinicians are not aware of it.
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http://dx.doi.org/10.1016/j.ando.2019.06.004DOI Listing
November 2019

La néoplasie endocrinienne multiple de type 1 : mise au point après le congrès de l’ENETS 2019: Multiple Endocrine Neoplasia Type 1: Development after the ENETS 2019 Congress.

Ann Endocrinol (Paris) 2019 Sep;80 Suppl 1:S19-S28

Service endocrinologie et maladies métaboliques, pôle cardio-vasculaire et métabolique, CHU Larrey-Rangueil, Toulouse, France.

Multiple Endocrine Neoplasia Type 1 (NEM1) is related to mutations of the menin gene. It is an autosomal dominant disease. Its prevalence is about 1/30 000 with a hugh penetrance. There is no genotype-phenotype correlation. This hereditary syndrome is characterized by the presence of tumors of the endocrine system (parathyroid, endocrine pancreas, pituitary and adrenal gland). Other disorders have also been described (bronchial and thymic carcinoid tumor, breast cancer, skin lesions). Management must take into account the specificities of these pathologies in NEM1 compared to sporadic forms (young age at diagnosis, multiple lesions within the same gland, multi-focal disease). © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.
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http://dx.doi.org/10.1016/S0003-4266(19)30113-1DOI Listing
September 2019

Gestational diabetes and acromegaly: Single-centre experience of 14 pregnancies.

Clin Endocrinol (Oxf) 2019 12 14;91(6):805-809. Epub 2019 Oct 14.

Service d'Endocrinologie, Maladies métaboliques et Nutrition, Pôle Cardio-Vasculaire et Métabolique, CHU Larrey, Toulouse, France.

Introduction: The prevalence of gestational diabetes (GD) in women with acromegaly is rarely reported. The aims of this study were to evaluate the prevalence of GD in acromegalic women submitted to a systematic screening for GD and then to compare women with or without GD.

Patients And Methods: We studied 14 pregnancies in 11 women (34.0 ± 3.6 years) treated with somatostatin analogues after a pituitary surgery (n = 6) or as primary (n = 5) therapy, and treatment was discontinued at the time of pregnancy diagnosis for 13 pregnancies. One woman was diagnosed with acromegaly during pregnancy and was treated with octreotide LAR between 12 and 18 weeks of gestation. Before pregnancy, no women had diabetes mellitus, and GH/IGF-1 hypersecretion was uncontrolled in 6 women.

Results: Gestational diabetes was diagnosed during 7 pregnancies (50%) in 6 women (one woman had GD during her 2 pregnancies), according to fasting blood glucose (n = 5) or to an oral glucose tolerance test (n = 2). Before pregnancy, IGF-1 was not controlled in 4 GD+ and in 2 GD- women. Women with GD were not significantly older and had increased pregestational BMI (P = .02), with a more frequent family history of type 2 diabetes, no personal history of GD but of macrosomia for one patient.

Conclusion: The prevalence of GD in our women is higher than that reported in the literature, probably resulting from the systematic GD screening and to the age of women. Therefore, routine screening of GD should be considered in women with acromegaly, particularly in those with risk factors for GD and with uncontrolled IGF-1 levels before pregnancy.
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http://dx.doi.org/10.1111/cen.14097DOI Listing
December 2019

Acquired von Willebrand's syndrome caused by primary hypothyroidism in a 5-year-old girl.

J Pediatr Endocrinol Metab 2019 Nov;32(11):1295-1298

Paediatric Endocrine Unit, Children's Hospital, Purpan University Hospital, Toulouse, France.

Background Acquired von Willebrand's syndrome (aVWS) associated with hypothyroidism is rare in children and more often diagnosed during the peripubertal period in the context of Hashimoto's thyroiditis. Case presentation A 5-year-old girl was referred to the paediatric haematology unit for rectal bleeding, anaemia and prolonged activated partial thromboplastin time (aPTT). Her developmental and learning skills were normal. The physical examination revealed severe short stature (height SDS: -3.6) with overweight (body mass index SDS: 1.8) and clinical sign of hypothyroidism. Laboratory investigation revealed aVWS type 1 associated with severe primary hypothyroidism. Anti-thyroid antibodies were negative and thyroid ultrasound found thyroid hypoplasia in favour of congenital hypothyroidism. Restoration of euthyroidism was associated with increased growth velocity and normalisation of coagulation parameters. Conclusion This report highlights the importance of excluding an underlying pathology (including hypothyroidism) in children with suspected VWS, even in young age.
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http://dx.doi.org/10.1515/jpem-2019-0082DOI Listing
November 2019

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome.

Clin Endocrinol (Oxf) 2019 11 13;91(5):669-675. Epub 2019 Sep 13.

Biochemistry and Genetic laboratory, Federative Institute of Biology, CHU Toulouse, Toulouse, France.

Background: DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low-to-moderate penetrance of tumour development, which is sex- and age-dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females.

Patients And Methods: We report a series of eight families referred for childhood-onset of MNG or DICER1-related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools.

Results: Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives.

Conclusions: Multinodular goitre is uncommon in children. Childhood-onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.
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http://dx.doi.org/10.1111/cen.14074DOI Listing
November 2019

Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 in Glucocorticoid-Resistant Patients.

J Clin Endocrinol Metab 2019 11;104(11):5205-5216

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche_S U1185, Faculty of Medicine at Université Paris-Sud, University Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France.

Context: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients.

Objective: We aim at studying the GR-mediated regulation of HSD11B2.

Design: The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11β-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme.

Results: Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11β-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11β-HSD2 catalytic activity.

Conclusion: Collectively, we demonstrate that 11β-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients.
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http://dx.doi.org/10.1210/jc.2019-00800DOI Listing
November 2019

Incidence of thyroid dysfunctions during treatment with nivolumab for non-small cell lung cancer: Retrospective study of 105 patients.

Presse Med 2019 Apr 17;48(4):e199-e207. Epub 2019 Apr 17.

CHU Larrey, Department of endocrinology and metabolic diseases, 31059 Toulouse, France. Electronic address:

Introduction: Immunotherapy is a standard not only in second line but also in first line treatment in patients with non-small cell lung cancer (NSCLC) and other tumors. Thyroid dysfunctions are the most common endocrine toxicities.

Objective: To determine the incidence of thyroid dysfunctions during treatment with a PD-1 monoclonal antibody (nivolumab) in patients with NSCLC.

Methods: Retrospective study of patients treated with nivolumab for NSCLC between May 2015 and December 2016; euthyroidism within the 3 months preceding immunotherapy; monitoring of thyroid function tests until stopping nivolumab, death or February 2017. Patients treated with levothyroxine, amiodarone or another immunotherapy were excluded.

Results: Among 183 patients treated, 105 fullfilled the inclusion criteria (72 males, median age: 61 years [range: 41-80]). Fifteen patients (14.3%) experienced a thyroid dysfunction; among them, compared to the "control" group (n=90), we found more females (53.3% vs. 27.8%; P=0.07), and younger patients (median age: 56 years vs. 62 years; P=0.02). Thirteen patients had thyrotoxicosis (median onset: 8 weeks), and then hypothyroidism was observed in 5 patients. Isolated hypothyroidism was rare (n=2) and late (median: 30 weeks). Three patients had anti-TPO antibodies. Three patients discontinued immunotherapy transiently due to thyroid dysfunctions. After a median follow-up of 9 months [95% CI, 7.5-10.3], one patient (6.7%) in the "thyroid dysfunctions" group and 30 patients (33.3%) in the "control" group died, with a trend toward a higher overall survival in the "thyroid dysfunctions" group (HR: 0.16 [95% CI, 0.02-1.15]; P=0.07).

Conclusion: Thyroid dysfunctions (isolated thyrotoxicosis, biphasic thyroiditis and hypothyroidism) were common, and required patients with NSCLC to be screened during nivolumab therapy.
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http://dx.doi.org/10.1016/j.lpm.2018.10.019DOI Listing
April 2019

Medical therapy in patients with endogenous hypoglycaemia: Is euglycaemia achievable?

Clin Endocrinol (Oxf) 2019 06 25;90(6):798-804. Epub 2019 Mar 25.

Service d'Endocrinologie, Maladies Métaboliques et Nutrition et Institut CardioMet, Centre Hospitalier Universitaire Rangueil-Larrey, Toulouse, France.

Context: While the only curative treatment for patients with endogenous hypoglycaemia related to inappropriate insulin or to insulin growth factor 2 (IGF2) secretion is surgery, medical treatment to normalize plasma glucose levels can be useful.

Objective: The aim of this prospective single centre study was to assess whether patients with endogenous hypoglycaemia, considered euglycaemic with medical treatments, experienced asymptomatic hypo- or hyperglycaemic excursions.

Patients And Methods: All patients with endogenous hypoglycaemia related to inappropriate insulin or to IGF2 secretion between 2012 and 2016 and considered normoglycaemic with medical treatment (absence of clinical hypoglycaemia and self-monitoring blood glucose in the normal range) were enroled and underwent a six-day continuous glucose monitoring (CGM) recording.

Results: Twenty-seven patients (inappropriate insulin secretion n = 25 and IGF2 secretion n = 2), treated with diazoxide (n = 16), somatostatin analogues (n = 7), glucocorticoids (n = 3) or a combination of these treatments (n = 1) were enroled. Twenty-five CGMs were analysed. CGM confirmed normoglycaemia in 11/25 patients (44%). Hypoglycaemias below 0.60 g/L were present in seven patients (28%) and were associated with hyperglycaemic excursions above 1.40 g/L in five patients. Seven patients (28%) had only hyperglycaemic excursions. Based on these results, treatment was modified in 14 patients (56%).

Conclusion: Despite the disappearance of hypoglycaemia-related clinical symptoms and normalization of blood glucose self-monitoring data, 56% of the patients with endogenous hypoglycaemia treated with medical therapy experienced asymptomatic hypo- and/or hyperglycaemia. Continuous glucose monitoring could be a useful approach to reveal and prevent hypo- or hyperglycaemic excursions.
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http://dx.doi.org/10.1111/cen.13961DOI Listing
June 2019