Maria Caroline Alves Coelho

Adverse effects of glucocorticoids: coagulopathy.

Hypercortisolism is associated with various systemic manifestations, including central obesity, arterial hypertension, glucose intolerance/diabetes mellitus, dyslipidemia, nephrolithiasis, osteoporosis, gonadal dysfunction, susceptibility to infections, psychiatric disorders, and hypercoagulability. The activation of the hemostatic system contributes to the development of atherosclerosis and subsequent cardiovascular morbidity and mortality. Previous studies have identified an increased risk of both unprovoked and postoperative thromboembolic events in patients with endogenous and exogenous Cushings syndrome (CS). The risk for postoperative venous thromboembolism in endogenous CS is comparable to the risk after total hip or knee replacement under short-term prophylaxis. The mechanisms that are involved in the thromboembolic complications in hypercortisolism include endothelial dysfunction, hypercoagulability, and stasis (Virchows triad). It seems that at least two factors from Virchows triad must be present for the occurrence of a thrombotic event in these patients. Most studies have demonstrated that this hypercoagulable state is explained by increased levels of procoagulant factors, mainly factors VIII, IX, and von Willebrand factor, and also by an impaired fibrinolytic capacity, which mainly results from an elevation in plasminogen activator inhibitor 1. Consequently, there is a shortening of activated partial thromboplastin time and increased thrombin generation. For these reasons, anticoagulant prophylaxis might be considered in patients with CS whenever they have concomitant prothrombotic risk factors. However, multicenter studies are needed to determine which patients will benefit from anticoagulant therapy and the dose and time of anticoagulation.

Bone Mineral Density and Microarchitecture in Patients With Autosomal Dominant Osteopetrosis: A Report of Two Cases

The aim of this case study is to describe changes in areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) scan, as well as volumetric bone density and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in two patients with autosomal dominant osteopetrosis (ADO) and compare with 20 healthy subjects. We describe a 44-year-old male patient with six low-impact fractures since he was age 16 years, and a 32-year-old female patient with four low-impact fractures on her past history. Radiographic changes were typical of ADO. Consistent with the much higher aBMD, total volumetric BMD (average bone density of the whole bone, including trabecular and cortical compartments) at distal radius and tibia (HR-pQCT) was more than twice the mean values found in healthy subjects in both patients. Trabecular number and thickness were higher, leading to an evident increase in trabecular bone volume to tissue volume. Also, an enormous increase in cortical thickness was found. Most important, a great heterogeneity in bone microstructure of the affected patients was evident on HR-pQCT images: islets of very dense bone were interposed with areas with apparent normal density. The increase in aBMD, volumetric BMD, and most indices of trabecular and cortical bone, associated with the great heterogeneity on bone tridimensional microarchitecture, reflect the accumulation of old and fragile bone randomly distributed along the skeleton. These alterations in bone microstructure probably compromise bone quality, which might justify the high prevalence of low-impact fractures in patients with ADO, despite abnormally elevated BMD.

Bone density and microarchitecture in endogenous hypercortisolism

Osteoporosis is a serious and underestimated complication of endogenous hypercortisolism that results in an increased risk of fractures, even in patients with normal or slightly decreased bone mineral density (BMD). Alterations in bone microarchitecture, a very important component of bone quality, may explain bone fragility. The aim of this study was to investigate bone density and microarchitecture in a cohort of patients with endogenous Cushings syndrome (CS).

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

Objective To describe the safety and efficacy of pegvisomant therapy and the predictors of treatment response in acromegaly patients at a single tertiary reference center in Brazil. Materials and methods We retrospectively reviewed the clinical, hormonal and radiological data of acromegaly patients treated with pegvisomant in our center. We also evaluated the presence of the d3 isoform of the growth hormone receptor (d3GHR). Results Twenty-seven patients were included (17 women). Pegvisomant was used in combination with octreotide LAR in 20 patients (74%), in combination with cabergoline in one (4%) and as monotherapy in six (22%). IGF-I normalization was achieved in 23 patients (85%). Mild and transitory elevation of liver enzymes was observed in two patients (7.4%), tumor growth in one (3.4%) and lipodystrophy in two (7.4%). One patient stopped the drug due to headaches. The GHR isoforms were evaluated in 14 patients, and the presence of at least one d3GHR allele was observed in 43% of them, but it was not a predictor of treatment response. Only pre-treatment IGF-I level was a predictor of treatment response. Conclusion Pegvisomant treatment was highly effective and safe in our series of Brazilian patients. A better chance of disease control can be expected in those with lower pre-pegvisomant IGF-I levels.

Rotation thromboelastometry and the hypercoagulable state in Cushing's syndrome.

Rotation thromboelastometry (ROTEM®) can be used for hypercoagulability evaluation. Cushings syndrome (CS) is associated with hypercoagulability; however, ROTEM® has never been evaluated in this setting.

The presence of nonfunctioning adrenal incidentalomas increases arterial hypertension frequency and severity, and is associated with cortisol levels after dexamethasone suppression test

There are limited data regarding the frequency of hypertension in nonfunctioning adrenal incidentaloma (NFAI). Our objectives were to investigate rates of hypertension and resistant hypertension in NFAI patients, and compare them to a control group without adrenal adenoma. We also aimed to evaluate the relationship between cortisol levels after 1 mg-dexamethasone suppression test (DST) and hypertension in NFAI patients. We selected 40 patients with NFAI and 40 control patients over the age of 18 without adrenal lesions on abdominal imaging. Data regarding hypertension, resistant hypertension, number, and type of antihypertensive drugs were collected from each subject. Blood samples for C-reactive protein (CRP), plasma adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEA-S) were also collected from the patients. Age, gender, race, smoking status, menopause status and BMI were comparable between patient and control groups. Patients with NFAI had a higher frequency of hypertension (72.5 vs. 47.5%; p = 0.04), resistant hypertension (37.9 vs. 11.1%; p = 0.04) and took three or more antihypertensive drugs (33.3 vs. 5.2%; p = 0.002) when compared to the controls, respectively. NFAI patients with hypertension had higher mean cortisol levels after 1 mg-DST when compared to NFAI patients without hypertension (1.3 ± 0.3 vs. 1.0 ± 0.4; p = 0.03, respectively). We found a negative correlation between cortisol levels after 1 mg-DST DHEA-S levels (r = −0.61; p < 0.001) and a positive correlation with CRP levels (r = 0.44; p = 0.02). In conclusion, NFAI patients presented a higher frequency of hypertension, resistant hypertension and used more antihypertensive medications when compared to the control group. We found an association between hypertension in NFAI patients and cortisol levels after 1 mg-DST.

ROLE OF IMAGING TESTS FOR PREOPERATIVE LOCATION OF PATHOLOGIC PARATHYROID TISSUE IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

OBJECTIVE Primary hyperparathyroidism (PHPT) can be cured by parathyroidectomy, and the preoperative location of enlarged pathologic parathyroid glands is determined by imaging studies, especially cervical ultrasonography and scintigraphy scanning. The aim of this retrospective study was to evaluate the use of preoperative cervical ultrasonography and/or parathyroid scintigraphy in locating pathologic parathyroid tissue in a group of patients with PHPT followed in the same endocrine center. METHODS We examined the records of 61 patients who had undergone parathyroidectomy for PHPT following (99m)Tc-sestamibi scintigraphy scan and/or cervical ultrasonography. Scintigraphic and ultrasonographic findings were compared to histopathologic results of the surgical specimens. RESULTS Ultrasonography detected enlarged parathyroid glands in 87% (48/55) of patients with PHPT and (99m)Tc-sestamibi scintigraphy in 79% (37/47) of the cases. Ultrasonography was able to correctly predict the surgical findings in 75% (41/55) of patients and scintigraphy in 72% (34/47). Of 7 patients who had negative ultrasonography, scintigraphy correctly predicted the surgical results in 2 (29%). Of 10 patients who had negative scintigraphy, ultrasonography correctly predicted the surgical results in 4 (40%). When we analyzed only patients with solitary eutopic parathyroid adenomas, the predictive positive values of ultrasonography and scintigraphy were 90% and 86%, respectively. CONCLUSION Cervical ultrasonography had a higher likelihood of a correct positive test and a greater predictive positive value for solitary adenoma compared to (99m)Tc-sestamibi and should be used as the first diagnostic tool for preoperative localization of affected parathyroid glands in PHPT. ABBREVIATIONS Ca = calcium IEDE = Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione PHPT = primary hyperparathyroidism PTH = parathyroid hormone.

Molecular evidence and clinical importance of β-arrestins expression in patients with acromegaly

β‐arrestins seem to have a role in endocytosis and desensitization of somatostatin receptor subtype 2 (sst2) and could be associated with the responsiveness to somatostatin receptor ligands (SRL) in patients with acromegaly. To investigate the in vivo correlation between β‐arrestins 1 and 2 with sst2, sst5 and dopamine receptor subtype 2 (D2) expressions, and the association of β‐arrestins with response to first‐generation SRL and invasiveness in somatotropinomas. β‐arrestins 1 and 2, sst2, sst5 and D2 mRNA expressions were evaluated by quantitative real‐time RT‐PCR on tumoral tissue of 96 patients. Moreover, sst2 and sst5 protein expressions were also evaluated in 40 somatotropinomas by immunohistochemistry. Response to SRL, defined as GH <1 μg/l and normal IGF‐I levels, was assessed in 40 patients. The Knosp‐Steiner criteria were used to define invasiveness. Median β‐arrestin 1, β‐arrestin 2, sst2, sst5 and D2 mRNA copy numbers were 478; 9375; 731; 156; and 3989, respectively. There was a positive correlation between β‐arrestins 1 and 2 (R = 0.444, P < 0.001). However, no correlation between β‐arrestins and sst2, sst5 (mRNA and protein levels) or D2 was found. No association was found between β‐arrestins expression and SRL responsiveness or tumour invasiveness. Although previous data suggest a putative correlation between β‐arrestins and sst2, our data clearly indicated that no association existed between β‐arrestins and sst2, sst5 or D2 expression, nor with response to SRL or tumour invasiveness. Therefore, further studies are required to clarify whether β‐arrestins have a role in the response to treatment with SRL in acromegaly.

Frequency of familial pituitary adenoma syndromes among patients with functioning pituitary adenomas in a reference outpatient clinic

IntroductionPituitary adenomas (PA) occur mainly as sporadic disease, but familial syndromes are found in approximately 5% of cases. Identification of these syndromes is important in order to diagnose individuals at risk at an earlier stage.AimsTo evaluate the frequency of familial PA in a reference outpatient clinic devoted to PA treatment and to identify family members suspected to have pituitary disease.MethodsPatients with PA were interviewed with respect to the presence of family members with diagnosis of PA or with signs or symptoms suggestive of them. The family members who had a clinical picture suggestive of pituitary disease were further evaluated in an attempt to identify new PA cases. In families with familial disease, the AIP gene was sequenced.Results262 patients were evaluated and familial syndrome was found in 13 (5%). Ten (3.8%) patients had familial isolated PA (FIPA) and three (1.2%) had multiple endocrine neoplasia type 1. After evaluation of family members’ symptomatology, 110 were considered suspected of having pituitary disease, but only 24 participated in the study. Of these 24, 1 was diagnosed with a corticotropinoma. AIP mutations were found in 20% of FIPA families.ConclusionWe found a frequency of familial PA similar to that previously described, as well as a similar frequency of AIP mutations among FIPA families. An active search of the affected family members was able to identify one case of Cushing´s disease. Patients should be aware of pituitary disease’s clinical picture to identify possibly affected family members.