Down-Regulation of the Mineralocorticoid Receptor (MR) and Up-Regulation of Hydroxysteroid 11-Beta Dehydrogenase Type 2 (HSD11B2) Isoenzyme in Critically Ill Patients.

Objective: The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period.Design: Prospective studySetting: One multi-disciplinary intensive care unit (ICU)Participants: Forty-two critically ill patientsMethods: Messenger RNA (mRNA) expression of MR, HSD11B1, and HSD11B2, aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls.Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period.Conclusion: Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states.

Histology is more ιmportant than persistent anti-Tg antibodies for progression of differentiated thyroid cancer.

CONTEXT: Anti-thyroglobulin antibodies (anti-Tg), present in 20%-25% of differentiated thyroid cancer (DTC) patients, interfere with thyroglobulin measurements posing a challenge in the follow-up. OBJECTIVES: The aim of this study was to identify clinical-histological factors that may affect anti-Tg persistence and disease outcome in DTC with positive anti-Tg. METHODS: We retrospectively studied 234 DTC patients, with positive anti-Tg at diagnosis (females: 82.1%, age at diagnosis: 46.0 ± 14.4 yrs, median follow-up: 5 yrs (1.5-32 yrs). 221/234 (94.4%) received radioiodine (RAI) ablation. Patients were divided into two subgroups: those whose anti-Tg became undetectable (anti-Tg-NEG) and those whose anti-Tg remained positive (anti-Tg-POS) at the end of the follow-up period. RESULTS: Anti-Tg-POS patients (n = 80, 34.2%) compared to anti-Tg-NEG (n = 154, 65.8%) had more frequently lymph node infiltration (36.3% vs 20.1%, P = .01), extrathyroidal extension (ETE, 35.0% vs 22.1%, P = .04), poorly differentiated DTC and increased tumour size (P ≤ .004). They received higher total RAI dose (P < .001). In most cases, additional RAI administration and/or additional surgeries did not lead to anti-Tg elimination. These had more frequently structural disease persistence/progression compared to anti-Tg-NEG (remission: 78.8% vs 95.5%, persistence: 13.8% vs 3.9%, progression: 7.5% vs 0.6%, P < .001). In Kaplan-Meier analysis, the probability of disease progression was higher in anti-Tg-POS. In Cox proportional hazard analysis, the predictors of disease progression were size (P = .002) and ETE (P = .006). CONCLUSIONS: Worse histological features are more frequent in patients with anti-Tg persistence during follow-up. Further additional RAI administration and/or surgeries do not affect anti-Tg elimination in most cases. Anti-Tg persistence correlates with structural persistence although tumour size and extrathyroidal extension are the main predictors of disease progression.

Longitudinal evaluation of glucocorticoid receptor alpha/beta expression and signalling, adrenocortical function and cytokines in critically ill steroid-free patients.

PURPOSE: Glucocorticoid actions are mediated by the glucocorticoid receptor (GCR) whose dysfunction leads to glucocorticoid tissue resistance. Our objective was to evaluate GCR-α and GCR-ß expression and key steps in the GCR signalling cascade in critical illness. METHODS: Expression of GCR and major GCR-target genes, cortisol, adrenocorticotropin (ACTH) and cytokines was measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age- and sex-matched subjects were used as controls. RESULTS: Acutely, mRNA expression of GCR-α was 10-fold and of GCR-ß 3-fold the expression of controls, while during the sub-acute phase expression of both isoforms was lower compared to controls. Expression of FKBP5 and GILZ decreased significantly. Cortisol levels remained elevated and ACTH increased during the 13-day period. CONCLUSIONS: GCR expression and hypothalamic-pituitary-adrenal axis function undergo a biphasic response during critical illness. The dissociation between low GCR expression and high cortisol implies an abnormal stress response.

Endocrine responses after a single bout of moderate aerobic exercise in healthy adult humans.

Exercise is a stress stimulus for the human organism affecting the homeostatic mechanisms of the body, depending on the type, duration, intensity and frequency of exercise. The aim of this study was to determine the effects of a moderate aerobic exercise bout on the Hypothalamo-Pituitary-Adrenal (HPA) axis acute hormonal responses in healthy adult humans. Twelve healthy male and female volunteers (age: 30.6 ± 4.4 years), performed a single bout of a 30-minute aerobic exercise at 70% of VO2max on a treadmill, following standard diet. Blood samples were collected before (t0), at the end of the exercise bout (t30), and 30 min after the completion of exercise (t60). Serum adrenocorticotropic hormone (ACTH), cortisol (COR), aldosterone (ALDO) and renin (REN) were measured. One-way ANOVA was used for statistics. ACTH and COR decreased after exercise, reaching significance (p < 0.01) 30 min after the completion of the exercise bout. ALDO increased at the end of exercise and remained elevated 30 min after its completion. REN significantly increased at the end of exercise (p < 0.05) and remained elevated. The exercise regimen used in this study had beneficial effects on the stress axis, suggesting that specific exercise protocols can be characterised by mild physiological stress-inducing effects hence be prescribed for special diseased populations.

Therapeutic trends and outcome of acromegaly: a single center experience over a 40-year period.

OBJECTIVE: To evaluate the therapeutic trends and long-term outcome of treatment modalities for acromegaly in our center over a 40-year period. DESIGN: We retrospectively studied 321 acromegalic patients (145 males/176 females) diagnosed and treated from the 1970s until September 2013. Patients were divided into two subgroups: group A consisted of 166 patients diagnosed before 1990 and group B of 155 patients diagnosed after 1990. Outcome was assessed with GH (random and/or post OGTT) and IGF1 measurements. RESULTS: More group A than group B patients were submitted to radiotherapy (57.8% vs 16.8% patients, respectively, p <0.001). In contrast, more patients of group B were offered surgery (70.3% vs 42.1% in group A, p <0.001) and/or medical treatment (70.3% vs 23.4% in group A, p <0.001). At latest follow-up, 68.4 % of patients in group B achieved GH <2.5 µg/l after treatment vs 39.8% in group A, p=0.001, 46.9% of patients in group B achieved GH <1 µg/l vs 20.3% in group A, p=0.001 and 47.1% of patients in group B achieved during OGTT GH nadir <0.4 µg/l vs 18.6% in group A, p=0.001. CONCLUSIONS: Transsphenoidal resection and medical treatment resulted in improved outcome in acromegalic patients treated over the last 20 years. However, the disease still remains uncontrolled in a considerable number of patients.

CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF PATIENTS WITH ECTOPIC ACTH SYNDROME DUE TO BRONCHIAL CARCINOID TUMORS: A ONE-CENTER EXPERIENCE.

OBJECTIVE: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department. METHODS: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure. RESULTS: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 ± 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin-releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 ± 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases. CONCLUSION: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence.

Prognostic importance of increased plasma amino-terminal pro-brain natriuretic peptide levels in a large noncardiac, general intensive care unit population.

The present study aimed to determine whether amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicts intensive care unit (ICU) mortality in a cohort of general, noncardiac, critically ill patients. To this end, a total of 233 consecutive mechanically ventilated patients (109 men) having a median age of 60 years and a wide range in admitting diagnoses, including medical (n = 118), surgical (n = 83), and multiple trauma (n = 32) cases were prospectively studied. Median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores on ICU admission were 16 and 9, respectively. The study end point was ICU outcome. Blood samples were drawn on admission in the ICU and on postadmission days 1 and 2 to determine NT-pro-BNP levels. In a subgroup (n = 77), admission proinflammatory and anti-inflammatory cytokine levels, including TNF-alpha, IL-6, and IL-10, were also measured. Nonsurvivors (n = 98) had significantly higher NT-pro-BNP levels than survivors (n = 135) on admission in the ICU (2,074 vs. 283 pg/mL; P < 0.001), on day 1 (2,197 vs. 221 pg/mL; P < 0.001), and on day 2 (2,726 vs. 139 pg/mL; P < 0.001). Median values for TNF-alpha, IL-6, and IL-10 were 3.70, 131.57, and 111.88 pg/mL, respectively. Receiver operating characteristic analysis showed that the area under the receiver operating characteristic curve in predicting ICU mortality was 0.70 for APACHE II and 0.77 for admission NT-pro-BNP (P = 0.08). The cutoff in admission NT-pro-BNP that best predicted outcome was 941 pg/mL. Multiple logistic regression analysis revealed that APACHE II score (odds ratio, 1.06; P = 0.007) and the best cutoff point in admission NT-pro-BNP (odds ratio, 7.74; P < 0.001) independently predicted ICU mortality, even if cytokines were entered in the analysis. In conclusion, plasma NT-pro-BNP is frequently raised in noncardiac, mixed, critically ill patients, and nonsurvivors have consistently higher levels than survivors. Elevated admission NT-pro-BNP represents an independent predictor for poor ICU outcome in the presence of clinical severity scores.