Aldo Iannelli

Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery

OBJECTIVES To evaluate whether patients with Cushings syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). DESIGN Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. PATIENTS AND METHODS Forty patients with active CS (36 with Cushings disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. RESULTS CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α(2) antiplasmin, P=0.0004, thrombin-antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α(2) antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushings pituitary adenoma had VTE (P=0.04). CONCLUSIONS Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol

OBJECTIVE Several tests have been proposed to diagnose patients with Cushings syndrome (CS). The aims of the study were: i) to evaluate the performance of salivary cortisol (SC) in hypercortisolism and ii) to compare SC with serum cortisol (SeC) and urinary cortisol. DESIGN AND PATIENTS This was a diagnostic study. Twenty-seven patients with untreated Cushings disease (CD untr), 21 women consuming oral contraceptive pill (OCP), 18 pregnant women, and 89 healthy subjects (controls) were enrolled. METHODS SC and SeC at baseline and after the low-dose dexamethasone suppression test (LDDST) and urinary free cortisol (UFC) were measured. RESULTS Midnight SC had a sensitivity of 100% in the CD untr group and a specificity of 97.7% in the controls. Specificity remained high (95.2%) in women taking OCP, while in pregnant women, it decreased to 83.3%. SC after the LDDST showed a sensitivity of 96.3% in the CD untr group; specificity was 97.7% in the controls and 90.5% in OCP women. Midnight SeC had a sensitivity of 100% in the CD untr group. SeC after the LDDST had a sensitivity of 100% in the CD untr group while specificity was 97.7% in the controls and 61.9% in women taking OCP. For UFC, sensitivity was 92.6% in the CD untr group while specificity was 97.7% in the controls and 100% in the OCP group. CONCLUSIONS SC is a reliable parameter for the diagnosis of severe hypercortisolism, with high sensitivity and specificity. In women during pregnancy or taking OCP, the measurement of SC, identifying the free fraction, could be helpful to exclude CS.

Diagnosis and treatment of autoimmune hypophysitis: A short review

Medical therapy of autoimmune hypophysitis with immunosuppressive drugs can be effective to induce remission of the disease by treating both pituitary dysfunction and compression symptoms. We describe the case of a 41-yr-old man with autoimmune hypophysitis in whom prednisone therapy induced remission of the disease but was followed by a sudden relapse after withdrawal. A second trial of corticosteroid was started and succeeded in inducing remission of the disease. Eight months after the second withdrawal pituitary function was restored, pituitary mass had disappeared, only partial diabetes insipidus remained unchanged. Review of the literature identified 30 articles, among case reports and case series, reporting a total of 44 cases of autoimmune hypophysitis treated with glucocorticoids and/or azathioprine. Combining all the cases, medical therapy resulted to be effective in reducing the pituitary mass in 84%, in improving anterior pituitary function in 45%, and in restoring posterior pituitary function in 41 %. Clinical aspects of autoimmune hypophysitis are discussed and a possible algorithm for the diagnosis and treatment of the disease is proposed.

CSF shunt removal in children with hydrocephalus.

SummaryThe possibility to remove a previously inserted CSF shunt device in hydrocephalic children is a well known though rare event for paediatric neurosurgeons. A retrospective analysis of our experience with a series of 850 children affected by non tumoral hydrocephalus shows that obvious shunt independence could be demonstrated in 3.2% of the patients (27 cases). The time interval between the CSF shunt insertion and removal ranged between 8 months and 12 years (mean: 8 years).Parameters analysed to search for any predictive elements were age at surgery, aetiology, type of prosthesis utilised, time interval between insertion and removal of the shunt, number of the possible revisions. The results of the study suggest that the highest incidence of shunt independence is reached in subjects operated on in early infancy, as 24 of 27 removed shunts were in patients operated on under 6 months of age, and the remaining in 2 children treated when less than 2 years old. Such a finding could be explained on the grounds of a delay in maturation of the CSF absorption mechanisms followed by a late normalisation in these patients.As regards to aetiology, 41% of the 27 patients considered in this series were affected by a post-haemorrhagic hydrocephalus, which was progressive, as demonstrated by serial neuroradiological examinations and echo-Doppler cerebral studies at the time of the surgical treatment. In six children the hydrocephalus was associated with myelomeningocele. Five patients had aqueduct stenosis and 2 communicating hydrocephalus.The types of CSF shunting system we utilised did not play any role in determining or facilitating shunt independence. No correlation was observed with the need and the number of shunt revisions. The role of the interval time between the insertion and the removal of the shunt was not analysable, because of the possible acquisition of the shunt independence prior to its demonstration at the moment of the surgical revision of the CSF shunt (elective lengthening because of the physiological body growth) or to the radiological demonstration of CSF shunt device disconnection. The same constraint prevents the evaluation of the actual overall incidence of shunt independence in shunted hydrocephalic children, as some of them could have harboured a non-functioning CSF shunt device, though unnoticed.

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study

OBJECTIVE Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. DESIGN AND METHODS The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. RESULTS Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43-1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (P=0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06-28.77, P=0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56-309.04, P=0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. CONCLUSIONS Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients.

Impact of different cut-off limits of peak GH after GHRH-arginine stimulatory test, single IGF1 measurement, or their combination in identifying adult patients with GH deficiency

OBJECTIVE To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD). DESIGN AND PATIENTS Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 μg/l) Endocrine Societies, by HypoCCs (2.5 μg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered. METHODS Peak GH after GHRH-Arg and IGF1. RESULTS Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD. CONCLUSIONS Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.

Tumor Infiltrating Lymphocytes But Not Serum Pituitary Antibodies Are Associated with Poor Clinical Outcome after Surgery in Patients with Pituitary Adenoma

CONTEXT Serum pituitary antibodies (Pit Abs) and tumor-infiltrating lymphocytes (TILs) have been described in pituitary adenomas, but their clinical significance remains unknown. OBJECTIVE The objective of the study was to assess Pit Abs and TILs prevalence in pituitary adenomas and their influence on clinical outcome. DESIGN This was a prevalence case-control study. PATIENTS AND SETTING Two hundred ninety-one pituitary adenoma cases (110 non-secreting, 30 ACTH-69 GH-71 prolactin- and 13 TSH-secreting adenoma; 177 operated and 114 untreated), 409 healthy controls, and 14 autoimmune hypophysitis were enrolled in a tertiary referral center. INTERVENTION Pit Abs were measured using immunofluorescence in all cases and controls (n = 714). The presence of TILs was evaluated using CD45 staining in a subset of adenomas surgically treated (n = 72). MAIN OUTCOME MEASURE Clinical response of pituitary adenoma after surgery was evaluated. RESULTS Pit Abs prevalence was higher in adenomas (5.1%) than healthy subjects (0.7%, P < 0.0001) and lower than in autoimmune hypophysitis patients (57%, P < 0.0001). Similarly, TILs prevalence was higher in adenomas than normal pituitary (P = 0.01) and lower than in autoimmune hypophysitis (P < 0.0001). No correlation between Pit Abs and TILs was found (P = 0.78). A poor clinical outcome was more common in adenoma patients with TILs (11 of 18, 61%) than in those without (17 of 54, 31%, P = 0.026). Multivariate regression analysis identified the presence of TILs as independent prognostic factor for persistence/recurrence of pituitary adenoma. CONCLUSIONS TILs and Pit Abs are present in a significant number of pituitary adenoma patients. Cell-mediated immunity appears to be predictive of a less favorable clinical outcome.

A functioning FSH-secreting pituitary macroadenoma causing an ovarian hyperstimulation syndrome with multiple cysts resected and relapsed after leuprolide in a reproductive-aged woman.

Bioactive gonadotropin-secreting pituitary adenomas are very rare in fertile women and can cause an ovarian hyperstimulation syndrome (OHSS). A 31-year-old woman with oligo-amenorrhea, severe ovarian cystic swelling and high serum estradiol was submitted to the resection of ovarian cysts and then treated with long-acting leuprolide 11.25 mg. Two months later, the ovarian multicystic hyperplasia relapsed, thus a pituitary MRI was performed and a pituitary macroadenoma was detected. In January 2010, she was referred to our Endocrinology Department where her hormonal evaluation showed high serum estradiol, FSH, α-subunit and inhibin with low LH. In April 2010, she underwent a trans-sphenoidal pituitary adenomectomy, which rapidly regularized the hormonal profile, the ovary and pituitary morphology and the menses. The case presented confirms that gonadotrophinomas occurring in reproductive-aged women frequently produce symptoms of ovarian hyperstimulation and proves that the use of GnRH analogs is not indicated in this condition.

Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella.

Objective: Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES. Design: In this case-control study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center. Methods: PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases. Results: PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p<0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02). Conclusions: The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Rathke's cleft cysts in children: clinical, diagnostic, and surgical features.

Rathke cleft cysts (RCCs) are malformative, benign lesions located in the sellar and/or suprasellar space; they are thought to arise from remnants of the Rathke pouch, where embryonic cells which are going to form the adenohypophysis join the nervous component that will become the neurohypophysis. These remnants may enlarge causing pituitary dysfunction and visual impairment. Cyst content may be a mucinous material of varying texture; the wall of the cyst is characterized by a well-differentiated, ciliated columnar epithelium. Magnetic resonance imaging (MRI) has increased sensitivity in RCCs radiologic diagnosis, even if symptoms related to the cyst are absent, so incidental findings are not unusual; in such cases, surgical therapy is questionable or not indicated. The prevalence of Rathke cleft cysts in children is considered lower than in adult population, in spite of their malformative nature, and young patients are mostly asymptomatic. We report a little series of symptomatic RCCs observed in children during an interval time of 4 years (2005–2008).