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Fengzhou Du, Qiao Chen, Xiaojun Wang, Xiaopeng Guo, Zihao Wang, Lu Gao, Xiao Long, and Bing Xing

Background

Facial abnormality is the most significant feature in acromegaly patients. However, it is unclear whether and how patient facial appearance improves after treatment. This study aimed to identify 3D facial changes in acromegaly patients after surgical treatment.

Methods

This study included 30 acromegaly patients who underwent resection of a pituitary GH adenoma. The location and extent of facial changes were identified by comparing baseline and 2-year follow-up 3D images of the face. Relationships between facial changes and GH and IGF-1 were evaluated with simple or multivariable linear regression models.

Results

Significant soft tissue improvements were observed in acromegaly patients with complete remission, especially in the nose and lip region. Significant reductions in nasal width (3.46 mm, P < 0.001), tip protrusion (1.18 mm, P = 0.003), face curve length (3.89 mm, P = 0.004) and vermilion area (1.42 cm3, P = 0.001) were observed at the 2-year follow-up. Further, changes in nasal width were associated with decreases in GH (β = 4.440, P = 0.017), the GH nadir (β = 4.393, P = 0.011) and IGF-1 (β = 5.263, P = 0.002). The associations were maintained after adjusting for confounders.

Conclusions

Acromegaly patients achieved considerable facial improvements after surgical treatment. The change in nose width was associated with GH and IGF-1 decrease. Better control of patient hormone levels after surgery improves patient facial recovery.

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Chin-Hsiao Tseng

Objectives

To investigate the metformin effect on the risk of osteoporosis (OS) and/or vertebral fracture (VF).

Methods

We enrolled 14 611 pairs of metformin ever and never users matched on propensity score (PS) from Taiwan’s National Health Insurance database. All patients had new-onset type 2 diabetes mellitus (T2DM) during 1999–2005 and were free from OS and/or any fracture at the start of follow-up on January 1, 2006. They were followed up until December 31, 2011 for the incidence of OS/VF. Cox regression incorporated with the inverse probability of treatment weighting using PS was used in the main analyses.

Results

New-onset OS/VF was diagnosed in 1757 never users (median follow-up 5.0 years) and 1143 ever users (median follow-up 5.3 years). The respective incidence rates were 2870.97 and 1713.20 per 100 000 person-years. Two-thirds of the incident cases had OS without VF and the other third had VF. In main analyses, the hazard ratio for ever vs never users was 0.592 (95% CI: 0.550–0.638). In either sex, a dose–response pattern was noted and metformin therapy > 2 years was consistently associated with a lower risk. The protective effect attenuated with increasing age but remained significant in patients aged ≥ 80 years. In sensitivity analyses, metformin significantly reduced the risk of both OS and VF (with or without a prior OS) by 30–40%. Additional analyses showed a null association for other antidiabetic drugs, but significant interactions between metformin and insulin, sulfonylurea and pioglitazone, respectively, were noted.

Conclusion

Metformin use is associated with a lower risk of OS/VF.

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Sabrina Chiloiro, Antonella Giampietro, Federica Mirra, Federico Donfrancesco, Tommaso Tartaglione, Pier Paolo Mattogno, Flavia Angelini, Lauretti Liverana, Marco Gessi, Anile Carmelo, Guido Rindi, Andrea Giustina, Maria Fleseriu, Alfredo Pontecorvi, Laura De Marinis, and Antonio Bianchi

Background

The treatment of acromegaly resistant to first-generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR.

Methods

Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (i) resistant to high dose first-generation SRLs and (ii) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded.

Results

Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4%) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P = 0.004, HR: 1.6, 95%CI: 1.2–4.6), with a Ki67-Li >4% (P = 0.004, HR: 3.49, 95%CI: 1.4–4.0) and with pre-treatment IGF-I >3.3×ULN (P=0.03, HR: 1.3, 95%CI: 1.1–6.0). A poor Pasireotide LAR response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P=0.025, HR: 1.6 95%CI: 1.4–3.4), pre-treatment IGF-I >2.3×ULN (P=0.049, HR: 2.4, 95%CI: 1.4–8.0), absent/low SST5 membranous expression (P=0.023 HR: 4.56 95%CI: 1.3–6.4) and in patients carried the d3-delated GHR isoform (P=0.005, HR: 11.37, 95%CI: 1.3–20.0).

Conclusion

Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR.

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Carole Harbulot, Soucounda Lessim, Dominique Simon, Laetitia Martinerie, Caroline Storey, Emmanuel Ecosse, Nicolas De Roux, Jean-Claude Carel, and Juliane Léger

Objective

Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP.

Design and methods

This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years.

Results

In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance.

Conclusion

These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

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Anastasia Gant Kanegusuku, Katherine Araque, Joanna Klubo-Gwiezdzinska, and Steven J Soldin

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Petros Perros, Krishnarajah Nirantharakumar, and Laszlo Hegedüs

Since the introduction of sensitive assays for serum thyroid-stimulating hormone (TSH) clinicians have advised hypothyroid patients to adjust the dose of levothyroxine (L-T4) in order to achieve a normal serum TSH. A minority of patients are dissatisfied with this treatment strategy and experience symptoms. Some indirect evidence suggests that a normal serum TSH may not necessarily reflect euthyroidism at the tissue level in patients treated with L-T4. Increasingly hypothyroid patients demand higher doses of L-T4 or liothyronine (L-T3) or animal thyroid extract, often purchased online, and titrate the dose against symptoms, although ample evidence suggests that combination treatment (L-T4 with L-T3) is no more effective than L-T4 alone. Community surveys show that up to 53% of treated hypothyroid patients at any time have a serum TSH outside the normal range. The recommendation by guidelines that the upper limit of the normal range for serum TSH should not be exceeded is supported by robust evidence and is generally accepted by clinicians and patients. However, until recently the lower limit of serum TSH for optimal L-T4 replacement has been controversial. New evidence obtained by two independent large population studies over the past two years has shown that mortality of hypothyroid patients treated with levothyroxine is increased when the serum TSH exceeds or is reduced outside the normal reference range. It is estimated that the implementation of a policy of normalising serum TSH in hypothyroid patients will reduce the risk of death of 28.3 million people in the USA and Europe alone.

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Rolf H H Groenwold and Olaf M Dekkers

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Ricarda von Krüchten, Roberto Lorbeer, Susanne Rospleszcz, Corinna Storz, Esther Askani, Charlotte Kulka, Wolfgang Rathmann, Annette Peters, Stefan Karrasch, Fabian Bamberg, Christopher Schlett, and Blerim Mujaj

Background

Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study.

Methods

From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors.

Results

In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = −12.43, P < 0.001), end-systolic volume (β = −7.12, P < 0.001), stroke volume (β = −5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = −0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes.

Conclusions

Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment.

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Aoife Garrahy, Martin Cuesta, Brian Murphy, Michael W O’Reilly, William P Tormey, Mark Sherlock, and Chris J Thompson

Objective

Severe hyponatraemia (plasma sodium concentration, pNa <120 mmol/L) is reported to be associated with mortality rates as high as 50%. Although there are several international guidelines for the management of severe hyponatraemia, there are few data on the impact of treatment.

Design and methods

We have longitudinally reviewed rates of specialist input, active management of hyponatraemia, treatment outcomes and mortality rates in patients with severe hyponatraemia (pNa <120 mmol/L) in 2005, 2010 and 2015, and compared the recent mortality rate with that of patients with pNa 120–125 mmol/L.

Results

Between 2005 and 2010 there was a doubling in the rate of specialist referral (32 to 68%, P = 0.003) and an increase in the use of active management of hyponatraemia in patients with pNa <120 mmol/L (63 to 88%, P = 0.02), associated with a reduction in mortality from 51 to 15% (P < 0.001). The improved rates of intervention were maintained between 2010 and 2015, but there was no further reduction in mortality. When data from all three reviews were pooled, specialist consultation in patients with pNa <120 mmol/L was associated with a 91% reduction in mortality risk, RR 0.09 (95% CI: 0.03–0.26), P < 0.001. Log-rank testing on in-hospital survival in 2015 found no significant difference between patients with pNa <120 mmol/L and pNa 120–125 mmol/L (P = 0.56).

Conclusion

Dedicated specialist input and active management of severe hyponatraemia are associated with a reduction in mortality, to rates comparable with moderate hyponatraemia.