ACTA ENDOCRINOLOGICA (BUC)

Context. Aromatase is a key enzyme in local estrogen production by androgen conversion, especially in women post-menopause. There have been controversies concerning aromatase localization in breast carcinomas and its association with current histopathological variables. Material and Methods. Using polyclonal antibody immunohistochemistry we assessed (by intensity and percentage scores) the immunolocalization of aromatase in 70 tissue samples, and described particularities within the molecular subtypes of breast cancer. Results. Aromatase was found in all tissue compartments: tumor (95.7%), stroma (58.6%) and adipose tissue (94.3%). Aromatase expression in tumor cells correlated inversely with tumor grading (p=-0.361, p=0.027), and positively with estrogen receptor status (ER, p=0.143, p<0.001). Dividing the study group by intrinsic subtypes, a strongly inversely association between tumor aromatase and grading (p=-0.486, p<0.001), and between stromal aromatase and Ki67-index (p=-0.448, p=0.048) was observed in luminal A breast cancer. Tumor aromatase and ER percentage scores had stronger correlations in luminal B HER2 negative (p=0.632, p=0.002), and positive (p=0.324, p=0.026) tumors. In contrast, in triple negative tumors, a positive association stromal aromatase and Ki67 index (p=- 0.359, p=0.007) was observed. Conclusion. Local aromatase was linked to better tumor differentiation and proliferation in luminal breast subtypes, and not in triple negative cases, suggesting a potential prognostic role of aromatase in breast carcinomas.

Context. Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, steatohepatitis (NASH) which can evolve with progressive fibrosis, cirrhosis and hepatocellular carcinoma. As liver biopsy cannot be used as a screening method, noninvasive markers are needed. Objective. The aim of this study was to test if there is a significant association between vitamin D deficit and the severity of NAFLD. Design. The patients were divided into two groups (vitamin D insufficiency/deficiency) and statistical analyses were performed on the correlation of clinical and biochemical characteristics with histopathological hepatic changes. Subjects and methods. We prospectively studied 64 obese patients referred for bariatric surgery between 2014 and 2016 to our Surgical Unit. Anthropometric, clinical measurements, general and specific biological balance were noted. NAFLD diagnosis and activity score (NAS) were evaluated on liver biopsies. Results. Increased serum fibrinogen was correlated with NASH (p=0.005) and higher NAS grade. T2DM was positively correlated with liver fibrosis (p=0.002). 84.37% of the patients had vitamin D deficit and 15.62% were vitamin D insufficient. Lobular inflammation correlated with vitamin D deficit (p=0.040). Fibrosis (p=0.050) and steatohepatitis (p=0.032) were independent predictors of low vitamin D concentration. Conclusions. Vitamin D status in conjunction with other parameters - such as T2DM - or serum biomarkers – namely fibrinogen level and PCR level - may point out the aggressive forms of NAFLD and the need for liver biopsy for appropriate management.

Introduction. Pheochromocytoma is a rare clinical finding during pregnancy. Due to the variable clinical presentation it may be mistaken for preeclampsia or primary hypertension. The early antenatal diagnosis is crucial, because it reduces possible maternal and fetal complications. Pheochromocytomas are usually benign, but may also present as or develop into a malignancy. Malignancy requires evidence of metastases at non-chromaffin sites distant from that of the primary tumor. Large tumor size and malignant disease are not necessarily associated. Case. The patient, a 39 years old multipara presented at 30 weeks of gestation with labile hypertension, headache and palpitations. She had a 6 years history of chronic hypertension controlled during the pregnancy with methyldopa. Using this treatment blood pressure was maintained at 140/100 mmHg. Further biochemical and radiological investigations confirmed the diagnosis of pheochromocytoma. The patient was invasively monitored and treated with alpha-adrenoblockers. Childbirth was performed by elective cesarean section at 34 weeks with simultaneous right-sided adrenalectomy. Postoperative period was uneventful. Histological examination of 12 cm encapsulated tumor revealed trabecular type pheochromocytma with focal capsular invasion. Although the usual criteria for malignancy, such as mitotic activity, nuclear pleomorphism, are not suitable to discern benign from malignant pheochromocytomas, we considered this large tumor presumably malignant in order to provide systematic longterm follow-up. Postoperative biochemical and imagistic screening was planned to detect and treat local recurrence or metastatic tumors. Conclusions. A multidisciplinary team to diagnose and treat pheochromocytoma during pregnancy is mandatory. Careful postoperative monitoring of recurrent disease is necessary indefinitely.

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A 62 years old woman was diagnosed with multinodular toxic goiter and primary hyperparathyroidism/ left parathyroid adenoma by hormonal assessment, ultrasound and nuclear thyroid/parathyroid scans. Cervical ultrasound illustrated a multinodular aspect of the thyroid with solid nodules and cystic-component nodules; the larger one represented a multinodular complex with necrosis areas in the left thyroid lobe, ACR TI-RADS score 4 (moderately suspicious). Functional nuclear imaging was performed for accurate differential diagnosis between thyroid vs. parathyroid localization, between cold vs. hot nodules, and eventually, for guiding the choice of a subsequent Fine- Needle Aspiration Biopsy (FNAB). Scans described an early intense 99mTc-sestaMIBI uptake with no 99mTc-pertechnetate uptake in the left thyroid lobe larger nodule. Due to the suspicion of malignancy for this nodule, we performed an additional scan (1 hour before the classical 2 hours parathyroid delayed scan). The intense uptake persists in both delayed scans suggesting no malignant phenotype and which was confirmed after surgery by benign histology. In conclusion, using a 99mTc-sestaMIBI personalized protocol, related to the radiotracer cellular uptake mechanisms: 1 hour scan (supplementary image, corresponding to the maximum uptake pattern of 99mTc-sestaMIBI for cancer cells) and 2 hours scan (for parathyroid washout evaluation) may avoid unnecessary extensive thyroid surgery.

Context. Accumulating data supports the key role of disrupted amino acids (AAs) metabolism in diabetes. Conflicting data regarding the relevance of serum AAs in diabetes and hypertension suggest that their relationship needs further investigation. Objective. To investigate serum AAs as biomarkers of increased BP variability evaluated during 24-hour ambulatory BP monitoring in the presence of type 2 diabetes. Design. Cross-sectional. Subjects and Methods. We analyzed serum AAs using targeted metabolomics (ultrahigh-performance liquid chromatography/mass spectrometry) in patients with type 2 diabetes (n=80). BP variability was assessed using 24-hour ambulatory BP monitoring. Participants were divided into two groups based on the 24-hour diastolic BP variability median value. Results. Aspartic acid, isoleucine, leucine, and phenylalanine were significantly lower, while glutamine was significantly higher in the group with higher diastolic BP variability (p-value <0.05 and variable importance in the projection >1). Corresponding pathways identified as disrupted in patients with diabetes and a higher 24-hour diastolic BP variability were phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and alanine, aspartate, and glutamate metabolism (pathway impact value >0). Conclusions. We identified specific changes in serum AAs and target AAs pathways in relation to increased 24-hour diastolic BP variability in patients with type 2 diabetes.

Introduction. Glucocorticoids (GC) are largely used for their anti-inflammatory and immunosuppressive effects. Until recently “local” administration (inhalation, topical, intra-articular, ocular and nasal) was considered devoid of important systemic side effects, but there is no administration form, dosing or treatment duration for which the risk of iatrogenic Cushing’s syndrome (CS) and consequent adrenal insufficiency (AI) can be excluded with certainty. Patients and methods. We present the case of a pregnant woman who developed overt CS with secondary AI in the second trimester of pregnancy. She had low morning plasma cortisol 6.95 nmol/L (normal non-pregnant range 166 – 507) and low ACTH level 1.54 pg/mL (normal range 7.2 – 63.3), suggestive for iatrogenic CS. A thorough anamnesis revealed chronic sinusitis long-term treated with high doses of intranasal betamethasone spray (6 - 10 applications/day, approximately 10 mg betamethasone/week, for 5 months). After decreasing the dose and switching to an alpha-1 adrenergic agonist spray, the adrenal function recovered in a few weeks without manifestations of AI. The patient underwent an uneventful delivery of a normal baby. A review of the literature showed that only a few cases with exogenous CS and consequent AI caused by intranasal GC administration were described, mostly in children, but none during pregnancy. Conclusion. Long-term high doses of intranasal GC may induce iatrogenic CS and should be avoided. Low levels of ACTH and cortisol should prompt a detailed anamnesis looking for various types of glucocorticoid administration.

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