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Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M Shoback, Antonio Sitges-Serra, Wim van Biesen, and Olaf M Dekkers

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.

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Garcilaso Riesco-Eizaguirre and Pilar Santisteban

Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.

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Mohsen Khosravi-Maharlooei, Ensiyeh Hajizadeh-Saffar, Yaser Tahamtani, Mohsen Basiri, Leila Montazeri, Keynoosh Khalooghi, Mohammad Kazemi Ashtiani, Ali Farrokhi, Nasser Aghdami, Anavasadat Sadr Hashemi Nejad, Mohammad-Bagher Larijani, Nico De Leu, Harry Heimberg, Xunrong Luo, and Hossein Baharvand

Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.

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Edoarda V A Albuquerque, Renata C Scalco, and Alexander A L Jorge

Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.

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Thierry Brue, Vincent Amodru, and Frederic Castinetti

With fewer than 200 reported cases, Cushing’s syndrome (CS) in pregnancy remains a diagnostic and therapeutic challenge. In normal pregnancies, misleading signs may be observed such as striae or hypokalemia, while plasma cortisol and urinary free cortisol may rise up to 2- to 3-fold. While the dexamethasone suppression test is difficult to use, reference values for salivary cortisol appear valid. Apart from gestational hypertension, differential diagnosis includes pheochromocytoma and primary aldosteronism. The predominant cause is adrenal adenoma (sometimes without decreased ACTH), rather than Cushing’s disease. There are considerable imaging pitfalls in Cushing’s disease. Aberrant receptors may, in rare cases, lead to increased cortisol production during pregnancy in response to HCG, LHRH, glucagon, vasopressin or after a meal. Adrenocortical carcinoma (ACC) is rare and has poor prognosis. Active CS during pregnancy is associated with a high rate of maternal complications: hypertension or preeclampsia, diabetes, fractures; more rarely, cardiac failure, psychiatric disorders, infection and maternal death. Increased fetal morbidity includes prematurity, intrauterine growth retardation and less prevalently stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism. Therapy is also challenging. Milder cases can be managed conservatively by controlling comorbidities. Pituitary or adrenal surgery should ideally be performed during the second trimester and patients should then be treated for adrenal insufficiency. Experience with anticortisolic drugs is limited. Metyrapone was found to allow control of hypercortisolism, with a risk of worsening hypertension. Cabergoline may be an alternative option. The use of other drugs is not advised because of potential teratogenicity and/or lack of information. Non-hormonal (mechanical) contraception is recommended until sustained biological remission is obtained.

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Stephan Petersenn, Albert Beckers, Diego Ferone, Aart van der Lely, Jens Bollerslev, Marco Boscaro, Thierry Brue, Paolo Bruzzi, Felipe F Casanueva, Philippe Chanson, Annamaria Colao, Martin Reincke, Günter Stalla, and Stelios Tsagarakis

Objective

A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease – including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.

Methods

We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.

Results

Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0–96.6%; median, 77.9%) and recurrence (0–47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.

Conclusions

The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.

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Cristina Capatina, Warrick Inder, Niki Karavitaki, and John A H Wass

Pituitary tumour apoplexy (PA) is a rare clinical syndrome that occurs as a result of acute haemorrhage and/or infarction within a frequently undiagnosed pituitary tumour. The sudden enlargement of the pituitary mass undergoing PA is responsible for a wide range of acute symptoms/signs (severe headache, visual loss, diplopia, hypopituitarism, impaired consciousness) which, together with the radiological evidence of a pituitary lesion, establish the diagnosis. The optimal care of PA requires involvement of a multidisciplinary team including endocrinologist, neurosurgeon, neuroophthalmologist and the management strategy that depends on the clinical manifestations, as well as the presence of co-morbidities. Prompt surgical decompression is initially indicated in cases with severe or progressive impairment of the visual acuity or the visual fields or with altered mental state and leads to visual and neurological recovery in most of the patients. The patients with mild, stable clinical picture (including those with isolated ocular palsies) can be managed conservatively (support of fluid and electrolyte balance and stress doses of steroids in most cases) with favourable visual and neurological outcome. Frequent reassessment is mandatory because the clinical course can be unpredictable; if progression of symptoms occurs, later elective surgery is indicated and is beneficial, especially in terms of visual outcome. The endocrinological outcome is less favourable, irrespective of the treatment option, with many patients remaining on long-term replacement therapy. Despite the above guidelines, clear proof of optimal outcomes in the form of randomised controlled trials is lacking. Regrowth of the pituitary tumour years after a PA episode is possible and patients require long-term surveillance.

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Faryal Mirza and Ernesto Canalis

Osteoporosis is a skeletal disorder characterized by decreased mass and compromised bone strength predisposing to an increased risk of fractures. Although idiopathic osteoporosis is the most common form of osteoporosis, secondary factors may contribute to the bone loss and increased fracture risk in patients presenting with fragility fractures or osteoporosis. Several medical conditions and medications significantly increase the risk for bone loss and skeletal fragility. This review focuses on some of the common causes of osteoporosis, addressing the underlying mechanisms, diagnostic approach and treatment of low bone mass in the presence of these conditions.

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Ernesto Canalis

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1–34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1–34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

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Jonàs Juan-Mateu, Olatz Villate, and Décio L Eizirik

Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.