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Emmanuelle Kuhn, Alexandra A Weinreich, Nienke R Biermasz, Jens Otto L Jorgensen, and Philippe Chanson

Context

Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence, restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis and surveillance is generally limited as the symptomatic growth is considered very rare.

Case descriptions

We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and micro-prolactinomas) complicated by apoplexy during pregnancy.

Conclusion

During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

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Livia Lamartina, Sophie Bidault, Julien Hadoux, Joanne Guerlain, Elizabeth Girard, Ingrid Breuskin, Marie Attard, Voichita Suciu, Eric Baudin, Abir Al Ghuzlan, Sophie Leboulleux, and Dana Hartl

Objective

The presence of extrathyroidal extension (ETE) is generally considered as an indication for total thyroidectomy for differentiated thyroid cancer. The accuracy of neck ultrasound for the diagnosis of ETE is controversial. The aim of this study was to assess the diagnostic accuracy of preoperative ultrasound evaluation of ETE.

Methods

The retrospective and observational study of consecutive patients operated between 2016 and 2019 for cytologically suspicious or indeterminate thyroid nodules were analyzed. US images obtained preoperatively were retrospectively reviewed to identify signs of minimal or gross ETE. Histology was considered as the golden standard for diagnosis of ETE. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV), and accuracy of US were evaluated.

Results

A cohort of 305 patients (75% females, median age 48 years) with 378 nodules (median size 18 mm) was studied. Seventy-five percent of the nodules (n = 228) were malignant on histology and ETE was present in 106 cases (28%): 83 minimal ETE and 23 gross ETE. Suspicion of minimal ETE on preoperative ultrasound was found in 50 (13%) with a sensitivity of 30%, a specificity of 93%, a PPV of 62% and an NPV of 78%, with an accuracy of 76%. Gross ETE on ultrasound was found in 19 (5%) nodules with a sensitivity of 78%, a specificity of 99.7% a PPV of 94.7% an NPV of 98.6% and an accuracy of 98%.

Conclusions

Preoperative US is very specific and accurate in diagnosing gross ETE which impacts the extent of initial surgery for thyroid cancers.

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Kazuki Ishiwata, Sawako Suzuki, Katsushi Igarashi, Yutaro Ruike, Kumiko Naito, Akiko Ishida, Hanna Deguchi-Horiuchi, Masanori Fujimoto, Hisashi Koide, Yusuke Imamura, Shinichi Sakamoto, Tomohiko Ichikawa, Jun-ichiro Ikeda, and Koutaro Yokote

Introduction

Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated.

Methods

To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers).

Results

All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation.

Discussion

A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation.

Conclusion

Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.

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Xiong-Fei Pan, Yichao Huang, Xinping Li, Yi Wang, Yi Ye, Huan Chen, Matti Marklund, Ying Wen, Yan Liu, Huayan Zeng, Xiaorong Qi, Xue Yang, Chun-Xia Yang, Ge Liu, Robert A Gibson, Shunqing Xu, Danxia Yu, Da Chen, Yuanyuan Li, Zhixiong Mei, An Pan, and Jason H Y Wu

Objective

We aimed to examine prospective associations between circulating fatty acids in early pregnancy and incident gestational diabetes mellitus (GDM) among Chinese pregnant women.

Methods

Analyses were based on two prospective nested case-control studies conducted in western China (336 GDM cases and 672 matched controls) and central China (305 cases and 305 matched controls). Fasting plasma fatty acids in early pregnancy (gestational age at enrollment: 10.4 weeks(s.d., 2.0)) and 13.2 weeks (1.0), respectively) were determined by gas chromatography-mass spectrometry, and GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Groups criteria during 24–28 weeks of gestation. Multiple metabolic biomarkers (HOMA-IR (homeostatic model assessment for insulin resistance), HbA1c, c-peptide, high-sensitivity C-reactive protein, adiponectin, leptin, and blood lipids) were additionally measured among 672 non-GDM controls at enrollment.

Results

Higher levels of saturated fatty acids (SFAs) 14:0 (pooled odds ratio, 1.41 for each 1-s.d. increase; 95% CI: 1.25, 1.59) and 16:0 (1.19; 1.05, 1.35) were associated with higher odds of GDM. Higher levels of n-6 polyunsaturated fatty acid (PUFA) 18:2n-6 were strongly associated with lower odds of GDM (0.69; 0.60, 0.80). In non-GDM pregnant women, higher SFAs 14:0 and 16:0 but lower n-6 PUFA 18:2n-6 were generally correlated with unfavorable metabolic profiles.

Conclusions

We documented adverse associations of 14:0 and 16:0 but a protective association of 18:2n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.

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Fabio Bioletto, Marco Barale, Mirko Parasiliti-Caprino, Nunzia Prencipe, Alessandro Maria Berton, Massimo Procopio, Désirée Deandreis, and Ezio Ghigo

Background

Primary hyperparathyroidism is characterized by an autonomous hypersecretion of parathyroid hormone by one or more parathyroid glands. Preoperative localization of the affected gland(s) is of key importance in order to allow minimally invasive surgery. At the moment, 11C-Methionine and 18F-Fluorocholine PET studies appear to be among the most promising second-line localization techniques; their comparative diagnostic performance, however, is still unknown.

Methods

PubMed/Medline and Embase databases were searched up to October 2020 for studies estimating the diagnostic accuracy of 11C-Methionine PET or 18F-Fluorocholine PET for parathyroid localization in patients with primary hyperparathyroidism. Pooled sensitivity and positive predictive value were calculated for each tracer on a 'per-lesion' basis and compared using a random-effect model subgroup analysis.

Results

In total, 22Twenty-two studies were finally considered in the meta-analysis. Of these, 8 evaluated the diagnostic accuracy of 11C-Methionine and 14 that of 18F-Fluorocholine. No study directly comparing the two tracers was found. The pooled sensitivity of 18F-Fluorocholine was higher than that of 11C-Methionine (92% vs 80%, P  < 0.01), while the positive predictive value was similar (94% vs 95%, P  = 0.99). These findings were confirmed in multivariable meta-regression models, demonstrating their apparent independence from other possible predictors or confounders at a study level.

Conclusion

This was the first meta-analysis that specifically compared the diagnostic accuracy of 11C-Methionine and 18F-Fluorocholine PET for parathyroid localization in patients with primary hyperparathyroidism. Our results suggested a superior performance of 18F-Fluorocholine in terms of sensitivity, while the two tracers had comparable accuracy in terms of positive predictive value.

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Lionne N Grootjen, Joost P H J Rutges, Layla Damen, Stephany H Donze, Alicia F Juriaans, Gerthe F Kerkhof, and Anita C S Hokken-Koelega

Objective

Scoliosis is frequently seen in children with Prader–Willi syndrome (PWS). There is still concern that growth hormone (GH) treatment might increase the risk of onset or progression of scoliosis. Short-term data suggested no adverse effects of GH on scoliosis, but long-term effects of GH treatment on development of scoliosis in PWS are unknown. This study investigated the effects of 8 years of GH treatment on scoliosis in children with PWS.

Design

Open-label, prospective cohort study in 103 children with PWS receiving GH for 8 years was analyzed. Prevalence and severity of scoliosis were compared to a group of 23 age-matched GH-untreated children with PWS.

Methods

Spine X-rays and DEXA-scans were performed, and Cobb angel was measured by two independent observers.

Results

After 8 years of GH treatment, at median age of 10.8 years, prevalence of scoliosis was 77.7%. No difference in prevalence or severity of scoliosis was found between GH-treated and age-matched untreated children with PWS (P = 0.409 and P = 0.709, respectively). Height SDS and trunkLBM were significantly higher in GH-treated children. Higher bone mineral density of the lumbar spine was found in children without scoliosis after 8 years of GH. Bone mineral apparent density of lumbar spine (BMADLS) SDS was associated with lower Cobb angle (r = −0.270, P = 0.008).

Conclusions

Eight years of GH treatment has no adverse effects on the prevalence and severity of scoliosis in children with PWS until 11 years of age. As BMADLS SDS is inversely associated with Cobb angle, it is pivotal to optimize the BMD status in children with PWS.

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Signe Stensen, Lærke S Gasbjerg, Liva L Krogh, Kirsa Skov-Jeppesen, Alexander H Sparre-Ulrich, Mette H Jensen, Flemming Dela, Bolette Hartmann, Tina Vilsbøll, Jens J Holst, Mette M Rosenkilde, Mikkel B Christensen, and Filip K Knop

Objective

The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved.

Design

A randomized, double-blinded, placebo-controlled, crossover study.

Methods

Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed.

Results

Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; −14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; −11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; −4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content.

Conclusions

Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.

Free access

Kazutaka Nanba and William E Rainey

Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes β-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.

Open access

Michael B Zimmermann and Maria Andersson

Iodine deficiency has multiple adverse effects on growth and development. Diets in many countries cannot provide adequate iodine without iodine fortification of salt. In 2020, 124 countries have legislation for mandatory salt iodization and 21 have legislation allowing voluntary iodization. As a result, 88% of the global population uses iodized salt. For population surveys, the urinary iodine concentration (UIC) should be measured and expressed as the median, in μg/L. The quality of available survey data is high: UIC surveys have been done in 152 out of 194 countries in the past 15 years; in 132 countries, the studies were nationally representative. The number of countries with adequate iodine intake has nearly doubled from 67 in 2003 to 118 in 2020. However, 21 countries remain deficient, while 13 countries have excessive intakes, either due to excess groundwater iodine, or over-iodized salt. Iodine programs are reaching the poorest of the poor: of the 15 poorest countries in the world, 10 are iodine sufficient and only 3 (Burundi, Mozambique and Madagascar) remain mild-to-moderately deficient. Nigeria and India have unstable food systems and millions of malnourished children, but both are iodine-sufficient and population coverage with iodized salt is a remarkable 93% in both. Once entrenched, iodine programs are often surprisingly durable even during national crises, for example, war-torn Afghanistan and Yemen are iodine-sufficient. However, the equity of iodized salt programs within countries remains an important issue. In summary, continued support of iodine programs is needed to sustain these remarkable global achievements, and to reach the remaining iodine-deficient countries.

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Luciana Martel-Duguech, Jorge Alonso-Pérez, Helena Bascuñana, Jordi Díaz-Manera, Jaume Llauger, Claudia Nuñez-Peralta, Paula Montesinos, Susan M Webb, and Elena Valassi

Introduction

Patients with acromegaly show musculoskeletal symptoms which may persist despite disease control. Increased i.m. fat fraction is a known cause of muscle dysfunction in several disorders.

Objective

To assess the degree of fat fraction in thigh muscles of controlled acromegaly patients and its relationship with muscle dysfunction.

Methods

In a cross-sectional study, we included 36 patients with controlled acromegaly and 36 matched controls. We assessed the percentage of fat fraction in each thigh muscle, using MRI 2-point Dixon sequence, and muscle performance and strength using the gait speed, timed up and go, 30-s chair stand, and hand grip strength tests. We evaluated joint symptoms using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC).

Results

Intramuscular fat fraction was greater in patients than controls (P < 0.05 for muscle compartments, rectus femoris (RF), vastus intermedius (VI), adductor magnus (AM) and semimembranosus). Patients had slower gait speed and poorer performance on the 30-s chair stand and timed up and go tests than controls (P < 0.05). The greater fat fraction in the combined anterior–posterior compartment and in each muscle was associated with worse performance on timed up and go (P < 0.05). The fat fraction in the anterior–posterior compartment predicted performance on timed up and go after adjusting for muscle area, IGF-I and WOMAC functional and pain scores (β = 0.737 P < 0.001).

Conclusions

Patients with controlled acromegaly have greater thigh i.m. fatty infiltration, which is associated with muscle dysfunction. Futures studies are needed to elucidate the mechanisms underlying this relationship.