Evaluation of screening practices for primary hyperaldosteronism by specialists and general practitioners: an observational, cross-sectional study

ABSTRACT Objective: Despite its recognized importance, primary hyperaldosteronism (PHA) remains an underdiagnosed condition in clinical practice. The objective of the present study was to evaluate PHA screening practices by general practitioners and specialists in endocrinology and cardiology. Subjects and methods: This cross-sectional, observational study invited physicians to respond voluntarily to an online survey. The survey collected the respondents' sociodemographic data and answers to five hypothetical clinical cases meeting Endocrine Society criteria for PHA screening. Results: In all, 126 physicians responded to the online survey. Endocrinologists were the specialists who most often chose PHA screening, although the screening rates were overall low, ranging from 36.5% to 92.9%, depending on the case and the respondents' specialty. The survey also assessed the reasons for not choosing PHA screening, which included limited availability of tests within the public health services, interference of antihypertensive medications on hormone levels, and failure to identify the screening indication. Being an endocrinologist was an independent predictor for choosing PHA screening for the patients in Cases #1 and #5 (p = 0.001 and p = 0.002, respectively). Conclusion: Endocrinologists were the specialists who most often chose PHA screening, although the screening rates were overall low among all specialists. These findings highlight a need for continuing medical education programs addressing PHA screening and making the diagnosis of PHA more present in the daily clinical practice of physicians treating patients with hypertension.

Adrenal incidentaloma: Do patients with apparently nonfunctioning mass or autonomous cortisol secretion have similar or different clinical and metabolic features?

OBJECTIVE: Although there is growing evidence associating nonfunctioning adrenal incidentalomas (NFAI) with cardiovascular risk factors, there are limited data whether NFAI and autonomous cortisol secretion (ACS) groups have similar or different clinical and metabolic features. The aim of this study is to compare cardiometabolic clinic parameters among patients with ACS and NFAI, as well as controls. DESIGN: Cross-sectional study. PATIENTS: Eighty nine NFAI, 58 ACS and 64 controls were evaluated. MEASUREMENTS: Diagnosis of NFAI (1 mg dexamethasone suppression test [1 mg-DST] ≤50 nmol/L [≤1.8 µg/dl]) and ACS (1 mg-DST > 50 nmol/L [> 1.8 µg/dl]) was established according to current guidelines. The control group was selected based on a normal adrenal imaging exam. RESULTS: There were no differences between groups regarding age, gender, ethnicity, menopause or body mass index. Patients with adrenal incidentaloma presented higher frequency of hypertension (74.1 vs. 57.8%; p = .02), resistant hypertension (45.4 vs. 9.4%; p < .001), dyslipidemia (80.1 vs. 63.9%; p = .01), as well as metabolic syndrome (84.2 vs. 61.7%; p = .001) compared to the controls, respectively. NFAI and ACS patients presented similar frequency of arterial hypertension (70.8 vs. 79.3%) and resistant hypertension (41.3 vs. 51.1%), dyslipidemia (79.3 vs. 81.5%) and metabolic syndrome (83.3 vs. 85.7%); also, levels of HbA1c were similar between the groups. Binary logistic regression showed that NFAI (p = .004) and ACS (p = .001) were independent predictors for resistant hypertension (p = .003); also, ACS was an independent predictor for metabolic syndrome (p = .04). CONCLUSIONS: NFAI and ACS presented a higher frequency of cardiometabolic morbidities in comparison with individuals with normal adrenal glands. Additionally, we demonstrated that both ACS and NFAI groups have similar cardiometabolic conditions.

Colonic tuberculosis presenting as intestinal subocclusion in a patient with neuroendocrine tumor: a case report.

Extra-pulmonary tuberculosis (EPT) is responsible for approximately 14% of all tuberculosis cases in Brazil. The incidence of EPT is increasing slightly and is often associated with human immunodeficiency virus infection and other causes of immunosuppression. The association of EPT and cancer is poorly documented. Here we present a rare case of intestinal subocclusion that was supposed to be caused by cancer and was caused by colonic tuberculosis (CT) in a patient with metastatic neuroendocrine tumor (NET). A 61-year-old woman presented with one-year history of abdominal pain, diarrhea and weight loss. An abdominal CT scan (ACTS) showed liver, peritoneal and lymph nodes metastasis. Colonoscopy revealed a subocclusive lesion in the descendent colon. She underwent an urgent laparoscopy and transverse colostomy. The liver biopsy revealed a well differentiated grade 2 NET and the mycobacterial culture confirmed tuberculosis in the colonic lesion. Anti-tuberculosis was prescribed, and somatostatin analogue therapy was introduced one month later. The tuberculosis treatment was finished, and the patient remained on somatostatin analogue for 21 months. During this time the symptoms of abdominal pain and diarrhea disappeared and her body weight increased 35% over her baseline weight. Then, diarrhea, flushing and abdominal pain returned, and a new ACTS confirmed progressive disease. Interferon was added to her treatment with satisfactory control of symptoms. She was forwarded to another hospital to be treated with 177Lu-DOTATOC. The symptoms improved and the patient remained symptom free for more than a year, and now she has a new disease progression. The patient will be evaluated for retreatment with 177Lu-DOTATOC. Advanced NET may be a devastating disease enough to predispose the patient to EPT. We must keep this hypothesis in the differential diagnosis of our patients since symptoms of CT are usually nonspecific. At colonoscopy, radiological features are strictures, colitis and polypoidal lesions and complications such as bowel perforation or fistula must be in mind. It is particularly important those with advanced disease in endemic areas of tuberculosis.

Bone Evaluation by High-Resolution Peripheral Quantitative Computed Tomography in Patients With Adrenal Incidentaloma.

CONTEXT: Data regarding high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with adrenal incidentaloma (AI) are unknown. PURPOSE: To evaluate the areal bone mineral density (aBMD), microstructure, and fractures in patients with nonfunctioning AI (NFAI) and autonomous cortisol secretion (ACS). METHODS: We evaluated 45 patients with NFAI (1 mg dexamethasone suppression test [DST] ≤1.8 µg/dL) and 30 patients with ACS (1 mg DST 1.9-5.0 µg/dL). aBMD was measured using dual-energy X-ray absorptiometry; vertebral fracture by spine X-ray; and bone geometry, volumetric bone mineral density (vBMD), and microstructure by HR-pQCT. RESULTS: Patients with ACS showed lower aBMD values at the spine, femoral neck, and radius 33% than those with NFAI. Osteoporosis was frequent in both groups: NFAI (64.9%) and ACS (75%). Parameters at the distal radius by HR-pQCT were decreased in patients with ACS compared to those with NFAI: trabecular vBMD (Tb.vBMD, P = 0.03), inner zone of the trabecular region (Inn.Tb.vBMD, P = 0.01), the bone volume/tissue volume ratio (BV/TV, P = 0.03) and trabecular thickness (P = 0.04). As consequence, a higher ratio of the outer zone of the trabecular region/inner zone vBMD (Meta/Inn.vBMD, P = 0.003) was observed. A correlation between the cortisol levels after 1 mg DST and Meta/Inn.vBMD ratio was found (r = 0.29; P = 0.01). The fracture frequency was 73.7% in patients with ACS vs 55.6% in patients with NFAI (P = 0.24). CONCLUSION: Our findings point to an association between trabecular bone microarchitectural derangement at the distal radius and ACS. Our data suggest that AI have a negative impact on bone when assessed by HR-pQCT, probably associated to subclinical hypercortisolism.

Adrenal Venous Sampling in Primary Aldosteronism: The Usefulness of Contralateral Suppression Index.

Adrenal venous sampling (AVS) is the gold standard test to differentiate the unilateral from the bilateral form in patients with primary aldosteronism (PA) although it may be a difficult procedure, especially the successful cannulation of the right adrenal vein. In this report, we describe a 49-year-old female patient diagnosed with PA, after investigating resistant hypertension and refractory hypokalemia. Abdominal computed tomography scan revealed a 2.5 cm adenoma on the right adrenal vein. AVS was performed under cosyntropin infusion. Aldosterone and cortisol concentrations were obtained from the right and left adrenal veins and inferior vena cava (IVC). Cortisol on each adrenal vein divided by cortisol on IVC confirmed successful cannulation of the left side only, which makes it impossible to calculate the lateralization index (LI). From the data on the left adrenal vein and IVC, the aldosterone-to-cortisol ratio divided by the IVC aldosterone-to-cortisol ratio was less than 1.0, suggesting that the left adrenal vein was suppressed with the excess aldosterone originating from the contralateral side (contralateral suppression index (CSI)). Right adrenalectomy was performed; postoperative hypoaldosteronism was confirmed. This report highlights the importance of CSI obtained in AVS when technical difficulties occur making it impossible to obtain LI, which is most commonly used to decide between surgical and clinical management of PA.

Gastrinoma of Cystic Duct: A Rare Association With Multiple Endocrine Neoplasia Type 1.

Neuroendocrine tumors (NETs) of cystic duct are extremely rare, accounting for less than 2% of NET cases. The association of biliary tree NET and multiple endocrine neoplasm type 1 (MEN1) are even more rare. In this report, we described a case of a 65-year-old woman who was referred to our neuroendocrine outpatient clinic to investigate MEN1 after an incidental diagnosis of gastrinoma. Her medical history initiated 7 years earlier with severe peptic disease not responsive to proton pump inhibitor therapy. Endoscopic study revealed erosive antral gastritis, erosive duodenitis, bulbar ulcer and pyloric deformity. During follow-up she presented with abdominal pain, chronic diarrhea and weight loss; an ultrasonography was performed and showed only a cholelithiasis. She underwent a video laparoscopic cholecystectomy and all her symptoms were solved. Histopathological study found a 1.0 cm well differentiated NET (Ki-67 labeling index < 2%) located in cystic duct infiltrating the entire wall and subserosa. The MEN1 investigation revealed a primary hyperparathyroidism with a brown tumor in right iliac bone; the patient was referred to a total parathyroidectomy with autotransplantation. No evidence of pituitary tumor was found. The patient remains asymptomatic 24 months after surgery. To conclude, this case highlights an unusual presentation of a cystic duct primary NET gastrinoma in a MEN1 context.

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.

Endocrine abnormalities in ring chromosome 11: a case report and review of the literature.

UNLABELLED: Ring chromosomes (RCs) are uncommon cytogenetic findings, and RC11 has only been described in 19 cases in the literature. Endocrine abnormalities associated with RC11 were reported for two of these cases. The clinical features of RC11 can result from an alteration in the structure of the genetic material, ring instability, mosaicism, and various extents of genetic material loss. We herein describe a case of RC11 with clinical features of 11q-syndrome and endocrine abnormalities that have not yet been reported. A 20-year-old female patient had facial dysmorphism, short stature, psychomotor developmental delays, a ventricular septal defect, and thrombocytopenia. Karyotyping demonstrated RC11 (46,XX,r(11)(p15q25)). This patient presented with clinical features that may be related to Jacobsen syndrome, which is caused by partial deletion of the long arm of chromosome 11. Regarding endocrine abnormalities, our patient presented with precocious puberty followed by severe hirsutism, androgenic alopecia, clitoromegaly, and amenorrhea, which were associated with overweight, type 2 diabetes mellitus (T2DM), and hyperinsulinemia; therefore, this case meets the diagnostic criteria for polycystic ovary syndrome. Endocrine abnormalities are rare in patients with RC11, and the association of RC11 with precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM has not been reported previously. We speculate that gene(s) located on chromosome 11 might be involved in the pathogenesis of these conditions. Despite the rarity of RCs, studies to correlate the genes located on the chromosomes with the phenotypes observed could lead to major advances in the understanding and treatment of more prevalent diseases. LEARNING POINTS: We hypothesize that the endocrine features of precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM might be associated with 11q-syndrome.A karyotype study should be performed in patients with short stature and facial dysmorphism.Early diagnosis and adequate management of these endocrine abnormalities are essential to improve the quality of life of the patient and to prevent other chronic diseases, such as diabetes and its complications.

ZAC1 and SSTR2 are downregulated in non-functioning pituitary adenomas but not in somatotropinomas.

INTRODUCTION: There are few data regarding ZAC1 expression in clinically non-functioning pituitary adenomas (NFPA). Because somatotropinomas and NFPA behave differently with respect to tumor shrinkage during somatostatin analogs (SA) therapy, we sought to compare the ZAC1 and somatostatin receptor (sstr) types 1, 2, 3 and 5 mRNA expression in these two pituitary adenoma subtypes and in normal human pituitaries. METHODS: ZAC1 and SSTR mRNA expression levels were evaluated using real-time RT-PCR (TaqMan) in 20 NFPA and compared with the expression levels in 23 somatotropinomas and five normal pituitaries. The NFPA invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Ki-67 and p53 were evaluated using immunohistochemistry. RESULTS: A total of 20 patients with NFPA [6 males, median age 56 years (range: 30-78)], 23 with acromegaly [12 males, median age 43 years (range: 24-57)] and five normal pituitaries [4 males, median age 48 years (range: 36-54)] were included. Four of the patients (20%) had Hardy's grade 2 tumors; all of the others had Hardy's grade 3 tumors. The Ki-67 median expression was 2.35 (range: 0.2-9.23), and only four of the tumors (20%) were positive for p53. The ZAC1 mRNA expression was significantly lower in NFPA than in somatotropinomas and in normal pituitaries (p<0.001 for both), as well as the SSTR2 (p=0.001 and 0.01, respectively). The SSTR3 expression was higher in the NFPA than in the somatotropinomas and in the normal pituitaries (p=0.03 and 0.02, respectively). No correlation was found between the ZAC1 mRNA expression and the tumor invasiveness, Ki-67 and p53. CONCLUSION: ZAC1 and SSTR2 are underexpressed and SSTR3 is overexpressed in NFPA compared to those in somatotropinomas and in normal pituitaries, which might explain the lack of tumor shrinkage that is observed in response to commercially available SA therapy in patients with NFPA.

Sellar and suprasellar mixed germ cell tumor mimicking a pituitary adenoma.

Germ cell tumors (GCT) are a heterogeneous group of lesions whose origin is not well established. Several cases of primary intrasellar germinomas have been reported, however non-germinomatous GCT have rarely been described. We report the case of a young adult male patient with a mixed GCT that presented with a sellar tumor with suprasellar extension. The patient seeked medical attention because of seizures and magnetic resonance imaging evidenced a tumor of the sellar region. Hyperprolactinemia was also present and dopamine agonist therapy was started. As there was a rapid tumor growth and the patient had concomitant central diabetes insipidus and elevated testosterone levels, a GCT was suspected and confirmed by elevated serum concentration of ß-human chorionic gonadotrophin. Patient underwent surgical resection of the tumor and histopathological examination confirmed the diagnosis of a mixed GCT. Chemotherapy was initiated, followed by conventional radiotherapy. In conclusion, although pituitary adenomas respond for the vast majority of sellar tumors, concomitant symptoms such as central diabetes insipidus and rapid tumor growth should raise the suspicion of a diverse diagnosis. The present report intend not only to show a rare case of sellar and suprasellar mixed GCT but also to remind clinicians that if laboratory findings do not fit into patient's diagnosis (such as high testosterone levels in our patient), then the diagnosis should be reviewed.

Familial isolated pituitary adenomas experience at a single center: clinical importance of AIP mutation screening / Experiência de um único centro em adenoma hipofisário familiar isolado: importância clínica do rastreio de mutação do AIP

We present four FIPA kindred discussing clinical and molecular data and emphasizing the differences regarding AIP status, as well as the importance of genetic screening. Family 1 consists of five patients harboring somatotropinomas with germline E24X mutation in AIP. In one of the patients, acromegaly was diagnosed through active screening, being cured by surgery. Families 2 and 3 are composed of two patients with non-functioning pituitary adenomas. Family 4 comprises patients harboring a prolactinoma and a somatotropinoma. No mutations in AIP were found in these families. No patient in Family 1 was controlled with octreotide treatment, while the acromegalic patient in Family 4 was controlled with octreotide LAR. In conclusion, FIPA is a heterogeneous condition, which may be associated with AIP mutation. Genomic and clinical screening is recommended in families with two or more members harboring pituitary adenomas, allowing early diagnosis and better outcome.

Apresentamos dados clínicos e moleculares de quatro famílias com adenoma hipofisário familiar isolado (FIPA) enfatizando as diferenças na presença ou não de mutação do AIP e a importância da triagem genética. A Família 1 é composta por cinco pacientes portadores de somatotropinomas com mutação germinativa E24X no AIP. Um dos pacientes foi diagnosticado por meio de rastreio ativo, com cura cirúrgica. As Famílias 2 e 3 apresentam em sua composição dois pacientes com adenomas hipofisários não funcionantes. A Família 4 compreende dois pacientes, um com prolactinoma e outro com somatotropinoma. Não foi encontrada mutação no AIP nessas famílias. Na Família 1, não houve resposta ao octreotide, enquanto o paciente acromegálico da Família 4 foi controlado com a medicação. Em conclusão, a FIPA é uma condição heterogênea que pode estar associada à mutação do AIP e o rastreio genético/clínico é recomendado nas famílias com dois ou mais membros portadores de adenoma hipofisário. Isso permite um diagnóstico precoce, com melhor prognóstico.

Familial isolated pituitary adenomas experience at a single center: clinical importance of AIP mutation screening.

We present four FIPA kindred discussing clinical and molecular data and emphasizing the differences regarding AIP status, as well as the importance of genetic screening. Family 1 consists of five patients harboring somatotropinomas with germline E24X mutation in AIP. In one of the patients, acromegaly was diagnosed through active screening, being cured by surgery. Families 2 and 3 are composed of two patients with non-functioning pituitary adenomas. Family 4 comprises patients harboring a prolactinoma and a somatotropinoma. No mutations in AIP were found in these families. No patient in Family 1 was controlled with octreotide treatment, while the acromegalic patient in Family 4 was controlled with octreotide LAR. In conclusion, FIPA is a heterogeneous condition, which may be associated with AIP mutation. Genomic and clinical screening is recommended in families with two or more members harboring pituitary adenomas, allowing early diagnosis and better outcome.

Utility of [(18)F] fluoro-2-deoxy-D: -glucose positron emission tomography in the localization of ectopic ACTH-secreting tumors.

Ectopically ACTH producing tumors may be difficult to localize by conventional radiology and functional imaging may be helpful. Case 1: 31-year-old man was diagnosed with ectopic ACTH-dependent Cushing's syndrome (ECS). Thorax CT revealed a 1.3 cm nodular opacity in upper left lobe, suggestive of residual lesion. [(18)F] fluoro-2-deoxy-D: -glucose ([(18)F] FDG) positron emission tomography ([(18)F] FDG PET) scan revealed mild glycolytic metabolic activity. Pathological examination confirmed an ACTH-positive carcinoid tumor. Case 2: 53-year-old woman presented with very rapid onset ECS. Pituitary MRI was normal. Thorax CT revealed no tumoral lesion. Abdominal and pelvic MRI showed images suggestive of hepatic and iliac, femoral and lumbar secondary implants. [(18)F] FDG PET scan revealed intense uptake in uterus, especially cervix, suggesting this to be the primary tumor site. These cases illustrate the role of [(18)F] FDG PET in the investigation of an ECS where conventional imaging studies were not elucidative in the search for a responsible tumor.