Milan Vrkljan

Endocrinological outcomes of pure endoscopic transsphenoidal surgery: a Croatian Referral Pituitary Center experience

Aim To analyze early remission, complications, and pituitary function recovery after pure endoscopic endonasal transsphenoidal surgery (PEETS), a novel method in pituitary adenoma treatment. Methods Testing of all basal hormone values and magnetic resonance imaging (MRI) were performed preoperatively and postoperatively (postoperative MRI only in nonfunctioning adenomas) in 117 consecutive patients who underwent PEETS in the period between 2007 and 2010. The series consisted of 21 somatotroph adenomas, 61 prolactinomas, and 4 corticotroph and 31 nonfunctioning adenomas. Sixty-three were macroadenomas and 54 were microadenomas. Remission was defined as hormonal excess normalization on the seventh postoperative day in functioning adenomas and as normal MRI findings approximately four months postoperatively in nonfunctioning adenomas. The presence of hypogonadism, growth hormone deficiency, and hypothyroidism was assessed on the seventh postoperative day. Hypocortisolism was assessed through necessity for replacement therapy within 18 months postoperatively. Results Remission was achieved in 84% of patients: in 100% of microadenoma and 70% of macroadenoma patients (P < 0.001, odds ratio [OR], 28.16, 95% confidence interval [CI], 1.61-491.36), respectively. Endocrinological complications occurred in 17.1% of patients: in 9% of microadenoma and 24% of macroadenoma patients (P = 0.049, OR, 3.06; 95% CI, 1.03-9.08). Duration of empirical hydrocortisone replacement therapy was significantly shorter in microadenoma patients (P < 0.001). Thirty-five percent of preoperatively present hormonal deficiencies improved after the surgery. Between tumor types there were no significant differences in remission, complications, and normal pituitary function recovery. Conclusion Patients with microadenomas had higher remission and lower complication rates following PEETS, emphasizing the necessity for early detection and treatment of pituitary adenomas. PEETS is a discussion-worthy method for microprolactinoma treatment.

Intrathyroid Parathyroid Carcinoma with Intrathyroidal Metastasis to the Contralateral Lobe: Source of Diagnostic and Treatment Pitfalls

Intrathyroidal parathyroid carcinoma is extremely rare clinical entity with potentially multiple diagnostic pitfalls. We report a case of 40-year-old man presented with classical manifestations of primary hyperparathyroidism, severe hypercalcemia and profoundly increased serum parathyroid hormone level. Neck ultrasonography demonstrated multinodular goiter with predominant 34 mm nodule in left thyroid lobe. Additional 16 mm nodule was found beneath the left lobe. Routine percutaneous fine-needle aspiration of predominant nodule indicated follicular thyroid carcinoma, while left inferior nodule was confirmed to be of parathyroid origin. The patient underwent surgery, during which frozen sections identified medullary thyroid carcinoma with metastasis to upper mediastinal lymph node. Permanent sections of the predominant left lobe nodule revealed intrathyroidal parathyroid carcinoma surrounded with multiple microscopic metastases. Left inferior nodule was metastatic lymph node. Additional 10 mm intrathyroidal metastasis of primary parathyroid carcinoma was found within right thyroid lobe. This case indicates that fine-needle-aspiration and intraoperative biopsy are of limited value in diagnosing parathyroid carcinoma, especially if localized intrathyroidally. Oncological en-block resection is treatment of choice, implying ipsilateral lobectomy in case of thyroid invasion. This firstly described case of intrathyroidal parathyroid carcinoma causing intrathyroidal dissemination may influence future treatment strategies.

Pituitary Metastasis Presenting as Ischemic Pituitary Apoplexy Following Heparin-induced Thrombocytopenia

Pituitary apoplexy (PA) typically results from infarction or hemorrhage in a pituitary adenoma, while PA in nonadenomatous pituitary gland is uncommon. Prothrombotic states have never been recognized as precipitating factors for PA. The authors report a case of an elderly female who received prophylactic fractionated heparin therapy due to sepsis, consequent rhabdomyolysis, and overt disseminated intravascular coagulation. On the seventh day of heparin therapy, she reported sudden vision loss, ptosis, diplopia, and severe headache. Severe thrombocytopenia and positive antibodies to the complex of platelet factor 4 and heparin confirmed heparin-induced thrombocytopenia type 2 (HIT). Magnetic resonance imaging disclosed a homogenous pituitary tumor mass with pronounced sphenoid sinus mucosa thickening and two hypointense zones within the tumor mass on contrast-enhanced images consistent with focal ischemic necrosis. The tumor was confirmed to be squamous cell carcinoma with no signs of necrosis. Ischemic necrosis was found within marginal pituitary tissue. This is the first reported case of ischemic PA associated with pituitary metastasis and the first case in which HIT triggered PA. Our case demonstrates that prothrombotic states such as HIT can precipitate ischemic PA. Pituitary metastasis can present with ischemic PA, but radiological features differ from those described in pituitary adenomas. Segregated low-signal intensity zones within the tumor mass on postcontrast images indicate partial infarction of the tumor, which could be a special feature of ischemic PA in pituitary metastasis and has never been described in pituitary adenomas. These are all novel findings and might enlighten the pathogenesis of PA.

Decrease in insulin resistance has a key role in improvement of metabolic profile during intragastric balloon treatment

To the Editor, Obesity is a chronic polygenic disease in most cases [1]. Despite the different pathogenesis, all obese individuals have something in common: low growth hormone (GH) levels and increased insulin levels [2]. This hormonal imbalance plays an important role in other metabolic disorders, such as glucose intolerance and dyslipidemia. Adipose tissue mass is also important factor. It is an endocrine organ that secrets several metabolic hormones and proinflammatory cytokines. The intensity of their secretion positively correlates with adipose tissue mass [3]. Weight loss improves metabolic profile, although the exact mechanism is poorly understood. A detailed study regarding this matter was published only 1 year ago. The authors disclosed that diet-induced weight loss increases GH and ghrelin levels and decreases insulin and leptin levels [2]. However, neither one study analyzed parallel changes in metabolic hormones and metabolic profile in short time intervals during weight loss. Hence, the exact causative relations between these hormones are unknown. BioEnterics intragastric balloon (BIB) is a endoscopic method in obesity treatment. The balloon placed in the stomach delays stomach emptying and enhances the feeling of satiety [4]. We aimed to investigate changes in serum insulin, C-peptide, GH, blood glucose, glycated hemoglobin, insulin resistance and lipid profile in first, third and sixth month after BIB placement. Since our previous study showed that the change in ghrelin and leptin levels during BIB treatment considerably depends on body mass index (BMI) [5], we analyzed those changes separately in obese (BMI \40 kg/m) and morbid obese (BMI \40 kg/m) patients.

Diabetic ketosis during hyperglycemic crisis is associated with decreased all-cause mortality in patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus have impaired ketogenesis due to high serum insulin and low growth hormone levels. Evidence exists that ketone bodies might improve kidney and cardiac function. In theory, improved ketogenesis in diabetics may have positive effects. We aimed to assess the impact of diabetic ketosis on all-cause mortality in patients with type 2 diabetes mellitus presenting with hyperglycemic crisis. We analyzed 486 patients with diabetic ketosis and 486 age and sex-matched patients with non-ketotic hyperglycemia presenting to the emergency department. Cox proportional hazard models were used to analyze the link between patient characteristics and mortality. During an observation time of 33.4 months, death of any cause occurred in 40.9 % of the non-ketotic hyperglycemia group and 30.2 % of the DK group (hazard ratio in the diabetic ketosis group, 0.63; 95 % confidence interval 0.48–0.82; P = 0.0005). Patients with diabetic ketosis had a lower incidence of symptomatic heart failure and had improved renal function. They used less furosemide and antihypertensive drugs, more metformin and lower insulin doses, all of which was independently associated with decreased mortality. Plasma glucose and glycated hemoglobin levels were similar in both groups. Patients with hyperglycemic crisis and diabetic ketosis have decreased all-cause mortality when compared to those with non-ketotic hyperglycemia. diabetic ketosis might be a compensatory mechanism rather than a complication in patients with hyperglycemic crises, but further prospective studies are warranted.

Obesity and hypercholesterolemia in patients with prolactinomas: Could DHEA-S and growth hormone be the missing link?

ABSTRACT Purpose: Increasing evidence exists that hyperprolactinemia alters metabolic profile. The mechanism of this effect is unknown. We aimed to investigate the differences between the metabolic profile of patients with prolactinomas and nonfunctional pituitary adenomas and to evaluate the impact of other pituitary hormones on their metabolic profile. Methods: Our retrospective study included 86 consecutive patients with prolactinomas and nonfunctional adenomas (29 prolactinomas and 57 adenomas). Body mass index (BMI), blood pressure, serum prolactin, growth hormone (GH), insulin-like growth factor I (IGF-I), adrenocorticotropic hormone (ACTH), cortisol, urinary free cortisol, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), dehydroepiandrosterone-sulfate (DHEA-S), testosterone in men, triglycerides, total cholesterol, HDL (high-density lipoprotein) cholesterol, LDL (Low-density lipoprotein) cholesterol, alanine-transaminase, aspartate-transaminase, fasting glucose, and C-reactive protein (CRP) were obtained for all patients. Regression analyses were performed on log-transformed data. Results: After adjustment for age, gender, and tumor size, prolactinomas were associated with higher BMI (OR 5.61, 95%CI 1.70–9.51, p = 0.005), LDL cholesterol (OR 3.60, 95%CI 1.35–5.93, p = 0.015), DHEA-S (OR 1.97, 95%CI 1.23–3.72, p = 0.026), and lower GH levels (OR 0.43, 95%CI 0.03–0.84, p = 0.037). In a linear multivariate regression, the association between DHEA-S, GH, and prolactin remained significant even after adjustment for BMI. GH and IGF-I were associated with BMI and LDL cholesterol, but the association diminished after adjustment for serum prolactin. Conclusions: Prevalence of obesity is four times higher in patients with prolactinomas than in patients with nonfunctional adenomas. Higher DHEA-S and lower GH levels in patients with prolactinomas may have an important role in prolactin-induced metabolic effects. Further studies are needed.

Diagnostic Accuracy of Perioperative Measurement of Basal Anterior Pituitary and Target Gland Hormones in Predicting Adrenal Insufficiency After Pituitary Surgery.

AbstractThe insulin tolerance test (ITT) is the gold standard for diagnosing adrenal insufficiency (AI) after pituitary surgery. The ITT is unpleasant for patients, requires close medical supervision and is contraindicated in several comorbidities. The aim of this study was to analyze whether tumor size, remission rate, preoperative, and early postoperative baseline hormone concentrations could serve as predictors of AI in order to increase the diagnostic accuracy of morning serum cortisol.This prospective study enrolled 70 consecutive patients with newly diagnosed pituitary adenomas. Thirty-seven patients had nonfunctioning pituitary adenomas (NPA), 28 had prolactinomas and 5 had somatotropinomas. Thyroxin (T4), thyrotropin (TSH), prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and insulin-like growth factor 1 (IGF-I) were measured preoperatively and on the sixth postoperative day. Serum morning cortisol was measured on the third postoperative day (CORT3) as well as the sixth postoperative day (CORT6). Tumor mass was measured preoperatively and remission was assessed 3 months after surgery. An ITT was performed 3 to 6 months postoperatively.Remission was achieved in 48% of patients and AI occurred in 51%. Remission rates and tumor type were not associated with AI. CORT3 had the best predictive value for AI (area under the curve (AUC) 0.868, sensitivity 82.4%, specificity 83.3%). Tumor size, preoperative T4, postoperative T4, and TSH were also associated with AI in a multivariate regression model. A combination of all preoperative and postoperative variables (excluding serum cortisol) had a sensitivity of 75.0% and specificity of 77.8%. The predictive power of CORT3 substantially improved by adding those variables into the model (AUC 0.921, sensitivity 94.1%, specificity 78.3%, PPV 81.9%, NPV of 92.7%). In a subgroup analysis that included only female patients with NPA, LH had exactly the same predictive value as CORT3. The addition of baseline LH to CORT3, increased sensitivity to 100.0%, specificity to 88.9%, PPV to 90.4%, and NPV to 100.0%.Besides CORT3, tumor size, thyroid hormones, and gonadotropins can serve as predictors of AI. LH in postmenopausal female patients with NPA has similar diagnostic accuracy as CORT3. Further studies are needed in order to validate the scoring system proposed by this study.

Changes in metabolic hormones after bariatric surgery and their predictive impact on weight loss

Although various metabolic hormones have been implicated in bariatric‐related weight loss, their use as predictors of weight loss is unknown. Our study evaluates changes in metabolic hormones after bariatric surgery, and their role as predictors of weight loss.

Complete response of adult-onset CNS Langerhans cell histiocytosis documented on 18F-FDG PET/CT.

We report a case of a 49-year-old woman with biopsy-proven multisystemic Langerhans cell histiocytosis (LCH) with hypothalamic involvement documented on F-FDG PET/CT. Chemotherapy with a combination of vinblastine, prednisolone, methotrexate, and 6-mercaptopurine was carried out. Two months later, a 90% reduction of the hypothalamic tumor mass was noted on magnetic resonance imaging, but with no signs of pathological F-FDG accumulation. The patient died 4 months later, and we found no signs of LCH on autopsy. Our case highlights the need for further studies regarding the role of F-FDG PET/CT in the assessment of treatment response in patients with LCH.

The possible role of stress induced hormonal disbalance in the patophysiology of insulin resistane in lean individuals

Insulin resistance (IR) is a common denominator of metabolic and hemodynamic disorders simultaneously present in one person and responsible for elevated risk of developing type 2 diabetes (T2DM) and cardiovascular incidents. According to the latest research, IR is present in 25-45% of the general population. Therefore, the mechanism of its development is in the center of scientific and professional interest. Established or acquired factors, or combinations thereof, which disturb any step of the physiological insulin action mechanism: its binding to the cellular receptor, through the complex cascade of intracellular signaling pathways might cause IR. Although the adiposity and its underlying risk factors are considered to be the primary cause of IR, it is present in a great porportion in lean individuals as well. There are insights of the possible role of psychological factors: exposure to stress and deprssion to IR development, although the mechanism of this relationship has not been comperhensively studied. Data driven from cell cultures and experimental animal models suggest that there is an elevated level of counter-regulatory insulin hormones: growth hormone, prolactin and cortisol due to acute stress exposure. However, the relationship between these psychological disorders with the hyperreactivity of the axis of the hypothalamic-pituitaryadrenal axis as the underlying mechanism in the patophysiology of IR in lean individuals has not been systematically investigated. Based on the aforementioned, we hypothesise that this mechanism would be responsible for the formation of IR, and consequently, T2DM in lean individuals. The possible effect of the amount of stress in conjunction with the serum concentration of growth hormone, cortisol, prolactin and dehydroepiandrostendone to the abnormal 5-h oral glucose tollerance test results could contribute to the primary prevention of diabetes and its complications.