Objective
Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences ...between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases.
Design
Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the
CASR
,
AP2S1
and
GNA11
genes.
Methods
Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated.
Results
We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger (
p
= 0.029), reported more frequently a positive family history (
p
< 0.001), presented higher magnesium (
p
< 0.001) and lower parathormone levels (
p
< 0.001) and were less often treated for hypercalcemia (
p
= 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709–0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826–0.991).
Conclusions
The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.
Summary The 85% of cases of primary hyperparathyroidism (PHPT) are due to parathyroid adenomas (PA) and less than 1% to parathyroid carcinomas (PC). The PA usually measure <2 cm, weigh <1 g and ...generate a mild PHPT, whereas the PC usually exceeds these dimensions and are associated with a severe PHPT. However, giant PA (GPA), which is defined as those larger than 3 g, has been documented. Those may be associated with very high levels of PTH and calcium. In these cases, their differentiation before and after surgery with PC is very difficult. We present a case of severe PHPT associated with a large parathyroid lesion, and we discuss the differential aspects between the GPA and PC. Learning points: In parathyroid lesions larger than 2 cm, the differential diagnosis between GPA and PC should be considered. Pre and postsurgical differentiation between GPA and PC is difficult; however, there are clinical, analytical and radiographic characteristics that may be useful. The depth/width ratio larger or smaller than 1 seems to be the most discriminatory ultrasound parameter for the differential diagnosis. Loss of staining for parafibromin has a specificity of 99% for the diagnosis of PC. The simultaneous presence of several histological characteristics, according to the classification of Schantz and Castleman, is frequent in PC and rare in GPA.
Summary Systemic thrombotic microangiopathy (TMA) is a serious condition whose early treatment is essential to reduce morbidity and mortality. TMA with only renal involvement has been associated with ...tyrosine kinase inhibitors, including lenvatinib, a drug used for certain advanced neoplasms. To date, TMA with systemic involvement associated with this drug has not been described. We present the case of a patient with progressive metastatic thyroid cancer who developed this complication after starting treatment with lenvatinib. We describe the signs and symptoms that led to the diagnosis and the treatment required for her recovery. Learning points Thrombotic microangiopathy (TMA) is a group of disorders characterized by thrombosis in capillaries and arterioles due to an endothelial injury. Both, localized and systemic forms have been described. TMA with systemic involvement is characterized by hemolytic anemia, low platelets, and organ damage. Vascular endothelial growth factor signaling inhibitors have been associated with TMA, either restricted to the kidney or with systemic involvement. Lenvatinib has been rarely associated with TMA. Although only forms with isolated or predominantly renal involvement had been described so far, a predominantly systemic form can occur. Lenvatinib-induced systemic TMA must be distinguished from primary forms by measuring ADAMTS-13. Treatment includes discontinuation of the drug and supportive measures. When anemia and thrombocytopenia coexist in a patient receiving treatment with lenvatinib, a peripheral blood smear to exclude TMA is recommended
Abstract Brain derived neurotrophic factor (BDNF) increases the levels of somatostatin (SS) and its mRNA. To test the hypothesis that the regulation of SS synthesis by BDNF occurs at the ...transcriptional level and requires specific promoter sequences, cerebrocortical and PC12trkB neurons were transiently transfected with different constructs of the SS promoter fused to the luciferase and CAT reporter genes. We demonstrated that BDNF triggered the transcription of the SS gene through the CRE sequence located in the SS promoter. BDNF and SS are genes regulated by K+ -induced neuronal activity. Using BDNF blocking antibodies, we investigated whether K+ -induced BDNF was required for K+ -dependent SS mRNA induction. We found that K+ -induced SS mRNA was partially prevented when BDNF was blocked. This finding indicated that BDNF mediated the induction of SS mRNA by K+ depolarization. To identify the mechanisms by which BDNF activates SS gene transcription we first elucidated the signaling pathways activated by BDNF in cerebrocortical cells. We confirmed that BDNF activates the MAPK/ERKs and PI3K/Akt pathways. Both signaling pathways are, in turn, implicated in the activation of CREB by BDNF. In addition we observed that the PKA inhibitors, H89 and Rp-cAMPS decreased BDNF-induced CREB activation. These findings suggested that BDNF-induced CREB activation was also mediated by the cAMP/PKA pathway. We next elucidated the mechanism by which BDNF induces SS mRNA. We observed that H89, PD0998059, KN62 and LY294002 diminished BDNF-induced SS mRNA suggesting that BDNF-induced SS mRNA is mediated by the activation of cAMP/PKA, MAPK/ERKs, CaMK and PI3K pathways.
Obesity results from an imbalance between food intake and energy expenditure, which leads to an excess of adipose tissue. The excess of adipose tissue and adipocyte dysfunction associated with ...obesity are linked to the abnormal regulation of adipogenesis. The objective of this study was to analyze the expression profile of cell-cycle- and lipid-metabolism-related genes of adipose tissue in morbid obesity.
We used a custom-made focused cDNA microarray to determine the adipose tissue mRNA expression profile. Gene expression of subcutaneous abdominal fat samples from 15 morbidly obese women was compared with subcutaneous fat samples from 10 nonobese control patients. The findings were validated in an independent population of 31 obese women and 9 obese men and in an animal model of obesity (Lepob/ob mice) by real-time RT-PCR.
Microarray analysis revealed that transcription factors that regulate the first stages of adipocyte differentiation, such as CCAAT/enhancer binding protein beta (C/EBPβ) and JUN, were upregulated in the adipose tissues of morbidly obese patients. The expression of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor which controls lipid metabolism and the final steps of preadipocyte conversion into mature adipocytes, was downregulated. The expression of three cyclin-dependent kinase inhibitors that regulate clonal expansion and postmitotic growth arrest during adipocyte differentiation was also altered in obese subjects: p18 and p27 were downregulated, and p21 was upregulated. Angiopoietin-like 4 (ANGPTL4), which regulates angiogenesis, lipid and glucose metabolism and it is know to increase dramatically in the early stages of adipocyte differentiation, was upregulated. The expression of C/EBPβ, p18, p21, JUN, and ANGPTL4 presented similar alterations in subcutaneous adipose tissue of Lepob/ob mice.
Our microarray gene profiling study revealed that the expression of genes involved in adipogenesis is profoundly altered in the subcutaneous adipose tissue of morbidly obese subjects. This expression pattern is consistent with an immature adipocyte phenotype that could reflect the expansion of the adipose tissue during obesity.
Insulin‐like growth factor I (IGF‐I) is a potent inducer of oligodendrocyte development and myelination. Although IGF‐I intracellular signaling has been well described in several cell types, ...intracellular mechanisms for IGF‐I‐induced oligodendrocyte development have not been defined. By using specific inhibitors of intracellular signaling pathways, we report here that the MAPK and phosphatidylinositol 3‐kinase signaling pathways are required for the full effect of IGF‐I on oligodendrocyte development in primary mixed rat cerebrocortical cell cultures. The MAPK activation, but not the phosphatidylinositol 3‐kinase activation, leads to phosphorylation of the cAMP response element‐binding protein, which is necessary for IGF‐I to induce oligodendrocyte development. cAMP, although it does not show any effect on oligodendrocyte development, has an inhibitory effect on IGF‐I‐induced oligodendrocyte development that is mediated by the cAMP‐dependent protein kinase. Furthermore, cAMP also has an inhibitory effect on IGF‐I‐dependent MAPK activation. This is a cAMP‐dependent protein kinase‐independent effect and probably contributes to the cAMP action on IGF‐I‐induced oligodendrocyte development.
Dopamine agonists (DA) are the first-line therapy in prolactinomas, but they fail to decrease prolactin (PRL) levels and/or tumor size in some of these tumors, which are labeled as resistant ...prolactinomas (RP). To date, risk factors for DA resistance are not fully understood and management of DA-RP is not well established.
We retrospectively recorded clinical, biochemical and radiological features, as well as management and outcome, of all cabergoline (CAB)-RP attended at the Endocrinology department of a tertiary hospital between 1995 and 2016. CAB resistance was defined as the failure to normalize PRL (biochemical resistance, BR) or reduce tumor size by at least 50% (morphological resistance, MR) with a CAB dose up to 2mg/week (or 3mg/week in cases where lower doses were not tested) for at least 3 months.
Ten CAB-RP were found. The mean age of the cohort was 30.6 years and 50% of subjects were male. The average tumor size was 1.78cm (80% macroadenomas). The mean maximal dose of CAB was 3.8mg/week. Five patients showed isolated MR, four combined MR+BR and only one isolated BR. MR patients were more often males and older than MR+BR patients. Transsphenoidal surgery achieved normalization of PRL and/or disappearance of tumor in three of seven patients. At the end of follow up all patients had controlled PRL levels (with or without CAB) and most of them bore a visible although stable tumor.
Isolated MR and combined MR+BR are the most frequent patterns of DA resistance whereas isolated BR seems to be uncommon. Our data support a high tumor size but not male gender as a risk factor for DA resistance.
Ectopic Cushing syndrome: Report of 9 cases Araujo Castro, Marta; Palacios García, Nuria; Aller Pardo, Javier ...
Endocrinologia, diabetes y nutricion,
05/2018, Letnik:
65, Številka:
5
Journal Article
Recenzirano
Abstract Introduction Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its ...management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years. Methods This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015. Results Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2840 μg/24 h and 204 pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up. Conclusions Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended.
Recently, there have been advances in understanding of the changes that occur in the hypothalamic-pituitary-adrenal axis during the different stages of critical disease. Such advances have led to a ...paradigm change, so that the aforementioned adaptations are no longer considered the result of adrenal axis activation, but a consequence of decreased cortisol metabolism illness. Knowledge of this new pathophysiological bases should lead to reconsider the diagnosis and treatment of adrenal insufficiency in critically ill patients, a condition poorly understood to date.
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