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Jacques Young, Magalie Haissaguerre, Oceana Viera-Pinto, Olivier Chabre, Eric Baudin and Antoine Tabarin

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.

Free access

Yutaka Takahashi

Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor-induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

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Giorgia Pepe, Domenico Corica, Luisa De Sanctis, Mariacarolina Salerno, Maria Felicia Faienza, Daniele Tessaris, Gerdi Tuli, Iris Scala, Laura Penta, Angela Alibrandi, Giovanni Battista Pajno, Tommaso Aversa, Malgorzata Wasniewska and the Thyroid Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED)

Objective

To evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents.

Design

Prospective multicenter study.

Methods

For the study, 101 DS patients with SH (TSH 5–10 mIU/L; FT4 12–22 pmol/L), aged 2–17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, and L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up.

Results

Thirty-seven out of 101 patients displayed autoantibody positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, P = 0.001; 32.4% vs 7.8%, P = 0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, P = 0.028). Gender, median BMI (SDS), height (SDS), FT4, and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (P = 0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (P = 0.02); and 37.8% of group A vs 51.5% of group B still had SH condition (P = 0.183). Logistic regression suggested autoimmunity (OR = 3.2) and baseline TSH values (OR = 1.13) as predictive factors of the evolution from SH to OH.

Conclusions

In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

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Nicholas A Tritos, Anders F Mattsson, Greisa Vila, Beverly M K Biller, Anne Klibanski, Srinivas Valluri, Judith Hey-Hadavi, Nicky Kelepouris and Camilo Jimenez

Objective

To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I).

Design

Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant).

Methods

Kaplan–Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk.

Results

The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02–1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population.

Conclusions

Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.

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Masanobu Fujimoto, Jane C Khoury, Philip R Khoury, Bhanu Kalra, Ajay Kumar, Patrick Sluss, Claus Oxvig, Vivian Hwa and Andrew Dauber

Objective

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors.

Design

Cross-sectional study at a single center.

Methods

PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3–18 years old) and an evaluation of the relationship between these proteins and anthropometric factors.

Results

In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = −0.58, −0.65; P < 0.0001).

Conclusions

This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.

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Yuan-Yuei Chen, Tung-Wei Kao, Chung-Ching Wang, Chen-Jung Wu, Yi-Chao Zhou and Wei-Liang Chen

Background

Cigarette smoking is a risk factor of osteoporosis and bone fracture. Tobacco smoke contains several polycyclic aromatic hydrocarbons. Thus, we hypothesized that environmental polycyclic aromatic hydrocarbon exposure is associated with bone loss and fracture risk. The present study examined the association between polycyclic aromatic hydrocarbon exposure and bone turnover in the general adult population.

Methods

A total of 1408 eligible participants from the National Health and Nutrition Examination Survey (NHANES 2001–2006) were included in this cross-sectional analysis. The levels of urinary N-telopeptide and serum bone-specific alkaline phosphatase, which are biomarkers of bone resorption and formation, respectively, were assessed. Meanwhile, polycyclic aromatic hydrocarbon exposure was evaluated using the concentrations of urinary polycyclic aromatic hydrocarbon metabolites. The association between polycyclic aromatic hydrocarbon exposures and N-telopeptide, and bone-specific alkaline phosphatase levels was assessed using a multivariate linear regression model.

Results

All polycyclic aromatic hydrocarbon metabolites except 3-phenanthrene were significantly associated with increased N-telopeptide levels (P < 0.05) after adjustment of relevant covariables. However, no significant relationship was observed between polycyclic aromatic hydrocarbon metabolites and bone-specific alkaline phosphatase levels. This relationship remained significant after the participants were assessed according to sex (P < 0.05). Additionally, all polycyclic aromatic hydrocarbon metabolites showed a positive association with N-telopeptide levels in participants aged <60 years (P < 0.05).

Conclusion

Polycyclic aromatic hydrocarbon exposure is associated with increased bone resorption among the general adult population in the United States. Further studies must assess the potential mechanisms associated with the adverse effects of polycyclic aromatic hydrocarbon exposure on bone loss.

Free access

Clemens Kamrath

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

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Yorinari Ochiai, Naoko Inoshita, Toshiro Iizuka, Hiroshi Nishioka, Shozo Yamada, Masanobu Kitagawa and Shu Hoteya

Objective

Patients with acromegaly are at increased risk of colorectal polyps. However, their risk of colorectal cancer remains unclear. This study aimed to identify the histopathological features of colorectal polyps in patients with acromegaly and compare their risk of colorectal cancer with that in healthy controls.

Methods

The study participants were 178 patients who underwent Hardy’s operation and perioperative colonoscopy at our hospital between April 2008 and September 2016. For the control group, we randomly selected 356 age- and sex-matched patients who underwent colonoscopy at our hospital during the same period. The incidence, size, location, and histology of the colorectal polyps detected were compared between the groups.

Results

Colorectal polyps were detected in 66.8% of the acromegaly group and 24.2% of the control group (P < 0.001). The average number and size of the polyps were 2.44 and 4.74 mm, respectively, in the acromegaly group and 1.77 and 3.89 mm in the control group (P = 0.001). Polyps in the acromegaly group were more likely to be in the rectosigmoid region (P = 0.006). In the acromegaly group, the frequency of polyps ≥5 mm was 34.3% and that for polyps ≥10 mm was 15.2%; the respective values were 7.6% and 2.2% in the control group (P < 0.001). We found no evidence of between-group histopathological differences in the polyp specimens resected by endoscopy.

Conclusions

Patients with acromegaly are at an increased risk of colorectal polyps, especially in the rectosigmoid region. However, there is no pathological evidence that they are at greater risk of colorectal cancer than the general population.

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J C Naafs, L M Vendrig, J Limpens, H J van der Lee, R G Duijnhoven, J P Marchal, A S van Trotsenburg and N Zwaveling-Soonawala

Objective

To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C).

Design

Systematic review with individual patient data (IPD) meta-analysis.

Methods

OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study.

Results

Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64–123). Mean weighted FSIQ was 97 (95% CI: 88–105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes.

Conclusion

A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Open access

Stinus Hansen, Niklas Rye Jørgensen, Anne Pernille Hermann and Rene Klinkby Støving

Objective

Roux-en-Y-gastric bypass (RYGB) surgery is an effective treatment for morbid obesity. A possible overlooked side effect is negative bone metabolic consequences.

Design

A seven-year prospective study following ten women and seven men after RYGB (baseline mean age 43 ± 8 years, BMI 42 ± 6 kg/m2).

Methods

Lumbar spine and total hip bone mineral density (BMD) using dual energy x-ray absorptiometry, distal radius and tibia bone geometry, volumetric BMD, microarchitecture and finite element estimated bone strength using high-resolution peripheral quantitative CT and biochemical markers of bone remodelling were assessed at baseline, 2 and 7 years.

Results

Compared to baseline, body weight was 24 ± 10% lower after 2 years and 21 ± 11% after 7 years. During the 7 years of follow-up, radius and tibia vBMD had declined 13 ± 8% and 8 ± 7% from baseline to 2 years and further 10 ± 7% and 7 ± 8% from 2 to 7 years (all P < 0.001). At both radius and tibia, cortical thickness declined and cortical porosity increased. From baseline to 7 years, there were clear indications of deteriorations of the trabecular network with fewer, more widely spaced and more in-homogeneously distributed trabeculae in both radius and tibia. Overall, declines in estimated bone strength of 16 ± 9% in radius and 16 ± 7% in tibia were observed (both P < 0.001).

Conclusion

Seven years after RYGB, evidence of continuous declines in BMD and ongoing deterioration of bone microarchitecture and reduced estimated bone strength compared to baseline and 2 years post-surgery results were found. These findings emphasize the need for regular assessment of bone health in patients with prior RYGB.