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Is diabetic neuropathy associated with increased risk of developing mental disorders?

Christopher Rohde, Nanna Brix Finnerup, Norbert Schmitz, Troels Staehelin Jensen, Reimar Wernich Thomsen, and Søren Dinesen Østergaard

Objective

It is largely unknown whether individuals with diabetic neuropathy face an increased risk of developing mental illness. Therefore, in a population-based cohort study, we aimed to examine whether individuals with diabetic neuropathy are at elevated risk of being diagnosed with a mental disorder compared to diabetes-duration-matched individuals without diabetic neuropathy.

Methods

We used the nationwide Danish registers to identify all individuals diagnosed with diabetic neuropathy between January 1, 1996, and January 1, 2019. For each of these individuals, we identified up to five individuals with diabetes, matched on the duration of illness, who were not diagnosed with diabetic neuropathy. We then compared incidence rates of mental disorders between individuals with diabetic neuropathy and the diabetes-duration-matched individuals using a Cox proportional-hazards model.

Restults

Individuals with diabetic neuropathy had a substantial and statistically significant increased risk of being diagnosed with any mental disorder (age- and sex-adjusted hazard rate ratio: 1.40, 95% CI: 1.31–1.48) as well as all specific mental disorders (psychotic disorder, bipolar disorder, unipolar depression, and/or anxiety disorder) compared with diabetes-duration-matched individuals without diabetic neuropathy.

Conclusions

Diabetic neuropathy appears to be associated with a substantially increased risk of developing a mental disorder. Knowledge of the potential mechanisms underlying this association could inform prevention and treatment and should therefore be pursued further.

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Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow up and genetic counseling?

Lucie Coppin, Sophie Giraud, Eric Pasmant, Arnaud Lagarde, Marie-Odile North, Lauriane Le Collen, Valérie Aubert, Gregory Mougel, Miriam Ladsous, Alyzée Louboutin, Hedia Brixi, Magalie Haissaguerre, Nicolas Schreyer, Marc Klein, Antoine Tabarin, Brigitte Delemer, Anne Barlier, Marie-Françoise Odou, and Pauline Romanet

MEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation, and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling.

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Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood

Melek Yildiz, Aysel Bayram, Firdevs Bas, Volkan Karaman, Guven Toksoy, Sukran Poyrazoglu, Feryal Gun Soysal, Semen Onder, Zehra Oya Uyguner, and Feyza Darendeliler

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients.

Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male.

Results: Median age at diagnosis of CAH was 5.7 years and markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected on pathological evaluation of gonadectomy materials in 4 patients (20%) (2 with simple virilizing 21-hydroxylase, 2 with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-size polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian “steroid cell tumors, not otherwise specified” and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient.

Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged ACTH exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Open access

The Pathophysiology of transient congenital hypothyroidism

Catherine Peters and Nadia Schoenmakers

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, e.g iodine deficiency and excess, anti- TSHR antibodies and exposure to anti-thyroid or iodine-rich medications may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Open access

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Hanna Nowotny, Uta Neumann, Véronique Tardy-Guidollet, S Faisal Ahmed, Federico Baronio, Tadej Battelino, Jérôme Bertherat, Oliver Blankenstein, Marco Bonomi, Claire Bouvattier, Aude Brac de la Perrière, Sara Brucker, Marco Cappa, Philippe Chanson, Hedi L Claahsen-van der Grinten, Annamaria Colao, Martine Cools, Justin H Davies, Helmut-Günther Dörr, Wiebke K Fenske, Ezio Ghigo, Roberta Giordano, Claus H Gravholt, Angela Huebner, Eystein Sverre Husebye, Rebecca Igbokwe, Anders Juul, Florian W Kiefer, Juliane Léger, Rita Menassa, Gesine Meyer, Vassos Neocleous, Leonidas A Phylactou, Julia Rohayem, Gianni Russo, Carla Scaroni, Philippe Touraine, Nicole Unger, Jarmila Vojtková, Diego Yeste, Svetlana Lajic, and Nicole Reisch

Objective

To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design and methods

A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results

Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4–5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions

This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

Open access

Primary hyperaldosteronism induces congruent alterations of sodium homeostasis in different skeletal muscles: a 23Na-MRI study

Martin Christa, Stefanie Hahner, Herbert Köstler, Wolfgang Rudolf Bauer, Stefan Störk, and Andreas Max Weng

Background

Sodium homeostasis is disrupted in many cardiovascular diseases, which makes non-invasive sodium storage assessment desirable. In this regard, sodium MRI has shown its potential to reveal differences in sodium content between healthy and diseased tissues as well as treatment-related changes of sodium content. When different tissues are affected disparately, simultaneous assessment of these compartments is expected to provide better information about sodium distribution, reduce examination time, and improve clinical efficiency.

Objectives

The objectives were (1) to investigate sodium storage levels in calf and pectoral muscle in healthy controls and patients and quantify changes following medical treatment and (2) to demonstrate homogeneous disruption in skeletal muscle sodium storage in patients with primary hyperaldosteronism (PHA).

Methods

We assessed sodium storage levels (relative sodium signal intensity, rSSI) in the calf and pectoral muscles of eight patients with PHA prior and after treatment and 12 age- and sex-matched healthy volunteers.

Results

Calf and pectoral muscle compartments exhibited similar sodium content both in healthy subjects (calf vs pectoral rSSI: 0.14 ± 0.01 vs 0.14 ± 0.03) and PHA patients (calf vs pectoral rSSI: 0.19 ± 0.03 vs 0.18 ± 0.03). Further, we observed similar treatment-related changes in pectoral and calf muscles in the patients (proportional rSSI change calf: 26%; pectoral: 28%).

Conclusion

We found that sodium was distributed uniformly and behaved equally in different skeletal muscles in Conn’s syndrome. This allows to measure both heart and skeletal muscle sodium signals simultaneously by a single measurement without repositioning the patient. This increases 23Na-MRI’s clinical feasibility as an innovative technique to monitor sodium storage.

Open access

Profiling steroid and thyroid hormones with hair analysis in a cohort of women aged 25 to 45 years old

Feng-Jiao Peng, Paul Palazzi, Sakina Mezzache, Nasrine Bourokba, Jeremie Soeur, and Brice M R Appenzeller

Objective

Endogenous hormones regulate numerous physiological processes in humans. Some of them are routinely measured in blood, saliva and/or urine for the diagnosis of disorders. The analysis of fluids may, however, require multiple samples collected at different time points to avoid the high variability in the concentration of some hormones. In contrast, hair analysis has been proposed as an interesting alternative to reveal average hormone levels over a longer period. In this work, we developed and validated an analytical method for analyzing 36 endogenous steroid and thyroid hormones and one pineal hormone in human hair using ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS).

Methods

Sample preparation involved hair decontamination, pulverization, methanol extraction, and purification with C18-solid phase extraction. Extracts were then divided into two portions, respectively injected into an UPLC-MS/MS system, and analyzed using two different instrumental methods. The method was applied to a healthy female population aged 25–45 years.

Results

The method was validated on supplemented hair samples for the 37 targeted hormones, and its application to the population under study allowed to detect 32 compounds in 2–100% of the samples. Complete reference intervals (2.5–97.5th percentiles) were established for estrone, 17β-estradiol, androstenedione, dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, cortisone, cortisol and 3,3’,5-triiodo-L-thyronine. Hair cortisone, cortisol, tetrahydrocortisone and tetrahydrocortisol concentrations were highly correlated with each other, with Kendall’s τ correlation coefficients ranging from 0.52 to 0.68.

Conclusion

Allowing the detection of 32 hormones from different chemical classes, the present method will allow to broaden hormonal profiling for better identifying endocrine disorders.

Restricted access

Prognostic value of dysnatremia for survival in neuroendocrine neoplasm patients

Julie Refardt, Tessa Brabander, Noémie S. Minczeles, Richard A Feelders, Wouter W de Herder, and Johannes Hofland

Objective: Hyponatremia and hypernatremia are common electrolyte abnormalities in patients with malignancy and have been independently associated with worse survival outcomes. To date, there are no data on the impact of dysnatremia on survival outcome in patients with neuroendocrine neoplasms (NENs).

Design: Retrospective cohort analysis from a tertiary care center of NEN patients treated with peptide receptor radionuclide therapy (PRRT) with a cumulative activity of at least 3.7 GBq 177Lu-DOTATATE between the years 2000 to 2015

Methods: Comparison of overall survival of patients with the occurrence of hyponatremia (serum sodium <135mmol/L) or hypernatremia (serum sodium >145mmol/L) before start or during PRRT.

Results: A total of 649 patients were included. Hyponatremia occurred in 57 patients during the observation period and was associated with a shorter median overall survival (95% CI) of 25 months (14-36) compared to 55 months (48-61) of the 512 normonatremic patients (p<0.001), adjusted hazard ratio (HR) 1.48 (95% CI: 1.04-2.12). Overall survival time was reduced regardless of whether hyponatremia was present at baseline or during PRRT.

In contrast, hypernatremia occurred in 80 patients and was associated with a longer median overall survival (95% CI) of 94 months (47-140) compared with the 512 normonatremic patients (p=0.018), adjusted HR 0.61 (95% CI: 0.40-0.92). This association was driven by the patients with hypernatremia during PRRT. No association between dysnatremia and progression-free survival after PRRT was observed.

Conclusions: The occurrence of hypo- or hypernatremia in PRRT-treated NET patients is associated with opposing outcomes with regard to overall survival. Sodium levels might have a prognostic role in these patients.

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Risk factors for second primary malignancies following thyroid cancer: a nationwide cohort study

Mijin Kim, Hyereen Kim, Sojeong Park, Jaeeun Joo, In Ju Kim, and Bo Hyun Kim

Objective

Thyroid cancer survivors have a high risk of second primary malignancies (SPMs). We aimed to evaluate the site-specific incidence, prognosis, and risk factors for metachronous SPMs following thyroid cancer.

Design

A nationwide cohort study.

Methods

This study included data from the Korea National Health Insurance Service (between 2002 and 2018). Exposure to diagnostic radiation was defined by the number of computed tomography (CT) and positron emission tomography-CT scans after the index date. A cumulative radioactive iodine (RAI) dose >100 mCi was considered high-dose RAI.

Results

During the median 6 years of follow-up, among 291 640 patients, 13 083 (4.5%) developed SPMs. Thyroid cancer survivors had a 26% increased risk of SPMs compared with the general population (standardized incidence ratio: 1.26; 95% CI: 1.22–1.29). Furthermore, those with SPMs had a significantly poorer survival rate than those without SPMs (hazard ratio: 11.85; 95% CI: 11.21–12.54; P  < 0.001). Significantly elevated risks were observed in myeloid leukemia and 13 solid cancer sites: lip, salivary gland, small intestine, larynx, lung, mediastinum and pleura, mesothelium, breast, corpus uteri, ovary, prostate, kidney, and bladder. Frequent diagnostic medical radiation exposure and high-dose RAI therapy were independent risk factors for several SPMs, including the cancer of salivary gland, lung, mediastinum and pleura, breast, kidney, and bladder, as well as myeloid leukemia.

Conclusions

Frequent diagnostic radiation exposure and high-dose RAI therapy are independent risk factors for SPM following thyroid cancer. Clinicians need to consider minimizing unnecessary diagnostic radiation exposure and administering a high dose RAI only when justified in patients with thyroid cancer.

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Skeletal muscle RUNX1 is related to insulin sensitivity through its effect on myogenic potential

Magdalena Stefanowicz, Agnieszka Nikolajuk, Natalia Matulewicz, Marek Straczkowski, and Monika Karczewska-Kupczewska

Objective: Skeletal muscle is the major site of insulin action. There are limited data on the relationship between insulin action and skeletal muscle myogenic/regenerative potential. RUNX1 is a transcription factor which plays a role in muscle development and regeneration. The aim of our study was to assess the role of skeletal muscle myogenic/regenerative potential in the development of insulin resistance through the studies on RUNX1 transcription factor.

Design: Cross-sectional study. Experimental part with myoblast cell line culture.

Methods: We examined 41 young healthy volunteers, 21 normal-weight and 20 with overweight or obesity. Hyperinsulinemic-euglycemic clamp and vastus lateralis muscle biopsy were performed. In L6 myoblast and human skeletal muscle myoblasts (hSkMM) cell cultures, Runx1 was silenced at 2 stages of development. Cell growth, the expression of markers of myogenesis, nuclei fusion index, Akt phosphorylation and glucose uptake were measured.

Results: Skeletal muscle RUNX1 expression was decreased in overweight/obese individuals in comparison with normal-weight individuals and was positively related to insulin sensitivity, independently of BMI. Runx1 loss-of-function at the stage of myoblast inhibited myoblast proliferation and differentiation, reduced insulin-stimulated Akt phosphorylation and insulin-stimulated glucose uptake. In contrast, Runx1 knockdown in myotubes did not affect Akt phosphorylation, glucose uptake and other parameters studied.

Conclusions: Myogenic/regenerative potential of adult skeletal muscle may be an important determinant of insulin action. Our data suggest that muscle RUNX1 may play a role in the modulation of insulin action through its effect on myogenesis.