Adrian Daly

Serum levels of soluble CD163 correlate with the inflammatory process in coeliac disease.

In coeliac disease, following the introduction of a gluten‐free diet, monitoring mucosal disease activity requires repeated small intestinal biopsies. If a test measuring a circulating inflammatory marker was available, this would be clinically valuable.

Functioning Pituitary Adenomas

Abstract Many molecular genetic abnormalities have been recognized in the setting of anterior pituitary adenomas. However, pituitary adenomas with heritable genetic causes are rare and have been described most often in the setting of an endocrine tumor syndrome, such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). MEN1 is an autosomal dominant condition that is associated with the occurrence of parathyroid, enteropancreatic, and anterior pituitary tumors. Endocrine-inactive tumors, such as lipomas and angiofibromas, are also frequently seen in MEN1 patients. The MEN1 gene on chromosome 11q13 encodes the nuclear protein, menin. MEN1 appears to act as a tumor suppressor gene, and recent data suggest that menin can potentially interact with thousands of genes, 3′ sites and in chromatin. To date, over 500 different individual mutations in the MEN1 gene have been described, most of which predict a truncated menin protein. However, in 20–30% of cases suggestive of MEN1 clinically, the MEN1 sequence is normal. About 40% of patients with MEN1 have pituitary adenomas, and 17% of cases present with a pituitary tumor. Patients with pituitary tumors present earlier than patients presenting with other MEN1 tumors. In families with MEN1, pituitary tumors are more frequent than in sporadic MEN1. From a clinical perspective, MEN1-associated pituitary adenomas are more aggressive and less responsive to treatment than sporadic non-MEN1 tumors.

Cellular effects of AP102, a somatostatin analog with balanced affinities for the hSSTR2 and hSSTR5 receptors

BACKGROUNDnSomatostatin analogs (SSAs) are first-line medical therapy for the treatment of acromegaly and neuroendocrine tumors that express somatostatin receptors (SSTR). Somatostatin suppresses secretion of a large number of hormones through the stimulation of the five SSTR. However, unbalanced inhibition of secretion as observed with the highly potent SSAs pasireotide causes hyperglycaemia mainly by inhibiting insulin secretion. In contrast, AP102 a new SSAs has neutral effect on blood glucose while suppressing GH secretion. Our objective was to establish the cellular effects of AP102 on SSTR2 and SSTR5 that may explain the differences observed between AP102 and other SSAs.nnnMETHODSnWe compared the binding and agonist activity of AP102 with somatostatin-14, octreotide and pasireotide in HEK293 cells transfected with human SSTR2 and SSTR5 receptors. SSAs signal transduction effects (cAMP concentrations) were measured in forskolin-treated cells in the presence of SSAs. Proliferation and apoptotic effects were determined and binding assays were performed using 125I- somatostatin-14.nnnRESULTSnAP102 has comparable affinity and agonist effect to octreotide at SSTR2 (IC50s of 112 pM and 244 pM, respectively; EC50s of 230 pM and 210 pM, respectively) in contrast to pasireotide that exhibits a 12-27 fold higher IC50 (3110 pM) and about 5-fold higher EC50 (1097 pM). At SSTR5, AP102 has much higher affinity and stimulating effect than octreotide (IC50s of 773 pM and 16,737 pM, respectively; EC50s of 8526 pM and 26,800 pM), and an intermediate affinity and agonist effect between octreotide and pasireotide. AP102, octreotide and pasireotide have variable anti-proliferative effects on HEK cells transfected with SSTR2 and SSTR5.nnnCONCLUSIONnAP102 is a new SSA that better reduces signaling at SSTR2 than SSTR5 and prevents cell proliferation at both receptors. The euglycaemic effect of AP102 observed in preclinical studies may be related to this intermediate agonistic potency between pasireotide and octreotide at SSTR2 and SSTR5.

The causes and consequences of pituitary gigantism

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.Pituitary gigantism is a rare growth disorder caused by excessive release of growth hormone and insulin-like growth factor 1. This Review discusses the diagnosis, genetic causes and clinical management of pituitary gigantism.Key pointsNearly 50% of patients with pituitary gigantism have a known underlying genetic cause; therefore, these patients should be strongly considered for genetic counselling and screening.Once growth hormone (GH) hypersecretion has been established, efforts should be made to avoid delays in instigating treatment to control levels of GH and insulin-like growth factor 1.A shorter time between diagnosis and the commencement of treatment is associated with a decreased final height in pituitary gigantism.Pituitary gigantism is a disease that predominantly affects males, but males also have a longer delay in time to diagnosis than females, leading to a low proportion of male patients who have disease control by 18 years of age.Somatotropinomas in pituitary gigantism are usually large (macroadenomas) and might be difficult to cure with surgery or medical therapy alone; therefore, multimodal approaches are common in pituitary gigantism.The effect of large tumour size and multiple surgeries and radiotherapy is that patients with pituitary gigantism often have hypopituitarism at long-term follow-up.

Chapter 4 – Functioning Pituitary Adenomas

Many molecular genetic abnormalities have been recognized in the setting of anterior pituitary adenomas. However, pituitary adenomas with heritable genetic causes are rare and have been described most often in the setting of an endocrine tumor syndrome, such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). MEN1 is an autosomal dominant condition that is associated with the occurrence of parathyroid, enteropancreatic, and anterior pituitary tumors. Endocrine-inactive tumors, such as lipomas and angiofibromas, are also frequently seen in MEN1 patients. The MEN1 gene on chromosome 11q13 encodes the nuclear protein, menin. MEN1 appears to act as a tumor suppressor gene, and recent data suggest that menin can potentially interact with thousands of genes, 3′ sites and in chromatin. To date, over 500 different individual mutations in the MEN1 gene have been described, most of which predict a truncated menin protein. However, in 20–30% of cases suggestive of MEN1 clinically, the MEN1 sequence is normal. About 40% of patients with MEN1 have pituitary adenomas, and 17% of cases present with a pituitary tumor. Patients with pituitary tumors present earlier than patients presenting with other MEN1 tumors. In families with MEN1, pituitary tumors are more frequent than in sporadic MEN1. From a clinical perspective, MEN1-associated pituitary adenomas are more aggressive and less responsive to treatment than sporadic non-MEN1 tumors.

Pituitary Tumors Associated With Multiple Endocrine Neoplasia Syndromes

Pituitary adenomas with a genetic predisposition account for approximately 5%–8% of all pituitary adenomas and the most frequent presentation is as familial isolated pituitary adenomas (FIPA). However, pituitary adenomas can occur in syndromic conditions that include several other endocrine and non-endocrine disorders. Among the multi-organ inherited or genetic forms of PAs the most frequent and best known are multiple endocrine neoplasia type 1 (MEN1) syndrome, the Carney complex (CNC), and the McCune Albright syndrome (MAS), which are due to mutations in MEN1 , PRKAR1A , and GNAS1 , respectively. Other less frequent syndromic presentations of PAs that occur in the setting of MEN4, 3PAs, and DICER1 syndrome (caused by mutations in CDKN1B , SDHx, and DICER1 genes, respectively) have also been described.

A prospective study of cardiac valvular status in patients treated with cabergoline for endocrine disease

ontre une anémie microcytaire avec une hyponatrémie sévère a 110 mEq/L, a TSH-3,58 mUI/L, non compatible à la T4L-2,90 ng/L (N-entre 7,1–18,5), le ortisol sérique effondré a 6 ng/mL, le reste du bilan hormonal (FSH-LH, PRL, H-IGF-1) était normal. ’échographie thyroïdienne montre une lobectomie droite associée à une atrohie inhomogène du lobe gauche, le TDM hypophysaire montre un aspect ompatible à une selle turcique vide, l’IRM n’a pas été faite faute de moyen. n traitement substitutif de son hypothyroïdie centrale et de son insuffisance urrénalienne (levothyrox/hydrocortisone) est instauré avec une amélioration linique et biologique très nette dans deux semaines. onclusion.– Cette observation illustre que l’hyponatrémie sévère peut avoir ne étiologie complexe qui nécessite des investigations qui coûte chère.

Genetic screening for AIP mutations in Young patients with sporadic and Familial Pituitary Macroadenomas

Screening for AIP mutations in patients <30 years of age with sporadic pituitary macroadenoma could improve clinical management of this population, according to results of a study published in the European Journal of Endocrinology. Mutations in the AIP gene, which encodes the aryl hydrocarbon receptor interacting protein, are frequent in patients with familial isolated pituitary adenomas (FIPA) but have also been reported in patients with other pituitary adenoma subtypes. Tumors arising from AIP mutations are large (macroadenomas) and occur at a young age. To evaluate the use of focused genetic screening, Tichomirowa et al. studied 163 patients with sporadic pituitary macroadenoma (≥10 mm maximal diameter on MRI) diagnosed when patients were aged <30 years. Other genetic causes or FIPA had been excluded. Germline AIP mutations were found in 11.7% of patients, and DNA sequence GENETICS