A Case Report of Severe Hypotonic Hyponatremia Secondary to Concomitant Intake of Desmopressin Replacement Therapy and Non-Steroidal Anti-Inflammatory Drugs

Background: Desmopressin (DDAVP) is an effective treatment of both polyuric conditions and bleeding disorders. Most of the data on safety profile of desmopressin (DDAVP) derives from studies on titration of drug treatment, whereas few reports describe severe side effects secondary to drug-drug interaction.Clinical case: We report the case of a 50-yr-old Caucasian man, affected with congenital central diabetes insipidus (DI), admitted to the Emergency Unit for ingravescent nausea, emesis and weakness since twelve hours. A recent endocrinological evaluation reported a normal anterior pituitary function. Shortly after admission, he developed an episode of generalized tonic-clonic seizure, resulting in coma. The post-critic physical examination did not showed clinical signs of volume expansion or depletion. Moreover, brain CT scan was normal. Based on his medical history and clinical findings, water intoxication secondary to non steroidal anti-inflammatory drug (NSAID) intake (ketoprofen, 200 mg/day for the last 3 days for cervical pain) concomitant with DDAVP replacement therapy (Minirin\uae 60 mcg 4 tablets a day) was hypothesized as cause of the severe euvolemic hypotonic hyponatremia observed at entry (natremia 113 mEq/l, n 135-145 mEq/l; plasma osmolality 238 mOsm/Kg, n 275-295 mOsm/Kg) and the acute fall in sodium levels was considered responsible for seizures and coma. After emergency procedures, the aquaretic tolvaptan (Samsca\uae 7.5 mg) was administered and hydratation was maintained according to water excretion. At the same time, desmopressin substitution was withdrawn. The patient completely recovered in 72 hours and was discharged 10 days after with reinstatement of desmopressin replacement therapy.Conclusions: Although several cases of hyponatremia in patients on DDAVP for different indications have been reported, no study has so far highlighted the potentially life-threatening side effects associated with NSAIDs intake during DDAVP replacement therapy for central diabetes insipidus. In order to improve DDAVP safety, risks and benefits of co-treatment should be carefully considered and therapeutic alternatives to NSAIDs should be recommended to patients with central diabetes insipidus

Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin : a case report and review of the literature

Most of the clinical data on the safety profile of desmopressin (DDAVP), which is an effective treatment for both polyuric conditions and bleeding disorders, originate from studies on the tailoring of drug treatment, whereas few reports exist describing severe side effects secondary to drug-drug interaction. We herein describe a case of severe hyponatremia complicated by seizure and coma due to the intake of non-steroidal anti-inflammatory drugs (NSAIDs) in a patient on DDAVP replacement therapy for central diabetes insipidus (DI). A 50-yr-old Caucasian man, with congenital central DI, developed an episode of generalized tonic-clonic seizure, resulting in coma immediately after being admitted to the Emergency Unit for weakness and emesis. Based on his medical history and clinical findings, water intoxication secondary to ketoprofen intake (200 mg/day for the last 3 days) concomitant with DDAVP replacement therapy (Minirin\uae 60 mcg 4 tablets a day) was hypothesized as being the cause of the severe euvolemic hypotonic hyponatremia (natremia 113 mEq/l, plasma osmolality 238 mOsm/Kg). After standard emergency procedures, appropriate gradual restoration of serum sodium levels to the normal range was achieved in 72 hours. Hydratation was maintained according to water excretion and desmopressin therapy was re-introduced. We discuss this case report in the context of the published literature. The present report first highlights the potentially life-threatening side effects associated with over-the-counter NSAIDs during DDAVP replacement therapy for central DI. Risks and benefits of co-treatment should be carefully considered and therapeutic alternatives to NSAIDs should be recommended to patients with central DI in order to improve DDAVP safet

Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas

Background: The optimal duration of cabergoline (CAB) treatment of prolactinomas that minimizes recurrences is not well established. 2011 Endocrine Society Guidelines suggested that withdrawal may be safely undertaken after 2\ua0years in patients achieving normoprolactinemia and tumor reduction. Materials: We analyzed 74 patients (mean age\ua0=\ua046.9\ua0\ub1\ua014.4, M/F\ua0=\ua019/55, macro/micro\ua0=\ua018/56) bearing a prolactinoma divided in 3 groups: group A (23) treated for 3\ua0years, group B (23) for a period between 3 and 5\ua0years, and group C (28) for a period >5\ua0years. CAB therapy was interrupted according to Endocrine Society Guidelines. Prolactin (PRL) levels were measured 3, 6, 12 and 24\ua0months after withdrawal. Recurrence was defined with PRL levels 6530\ua0ng/ml. Results: Groups did not differ in pretreatment PRL levels (123.2\ua0\ub1\ua0112.1, 120.9\ua0\ub1\ua0123.8, 176.6\ua0\ub1\ua0154.0), pituitary deficit (4, 17, 17\ua0%), mean CAB weekly dose (0.7\ua0\ub1\ua00.4, 0.6\ua0\ub1\ua00.3, 0.7\ua0\ub1\ua00.4) and PRL levels before withdrawal (17.1\ua0\ub1\ua019.6, 11.4\ua0\ub1\ua08.8, 13.8\ua0\ub1\ua013.5). Recurrence occurred within 12\ua0months in 34 patients (45.9\ua0%), without significant differences among groups. Neuroradiological evaluation showed a significantly higher presence of macroadenoma in group C (13, 17 and 39\ua0%, respectively). Recurrence rate of hyperprolactinemia did not depend on sex, tumor size or CAB dose but it was significantly correlated with PRL levels at diagnosis and before withdrawal (p\ua0=\ua00.03). Finally, patients with pituitary deficit at diagnosis showed a significantly higher recurrence rate (p\ua0=\ua00.03). Conclusions: The study provides additional evidence that prolonging therapy for more than 3\ua0years does not reduce recurrence rate. In particular, recurrence risk was similar in micro- and macroadenomas, and higher in patients with pituitary deficits at diagnosis

Hypothalamic-Pituitary Axis in Non-Functioning Pituitary Adenomas : focus on the Prevalence of Isolated Central Hypoadrenalism

Introduction: Non-functioning pituitary adenomas (NFPA) account for about 40% of pituitary tumors. Pituitary deficiencies are present at diagnosis in 60-80% of NFPA, and, classically, growth hormone (GH) secretion is lost first, while adrenocorticotropic hormone is expected to disappear last. The aim of this study was to evaluate the incidence of multiple or isolated pituitary deficiencies in a large series of NFPA. Materials and Methods: We retrospectively analyzed data on 218 NFPA cases (59% females, 59% with macroadenomas, average age: 50.2 \ub1 17 years) followed up at our center from 1990 to 2013. At diagnosis all patients had a complete evaluation of pituitary function in basal conditions and provocative tests for the hypothalamic-pituitary-adrenal axis, while tests for GH deficiency (GHD) were carried out in 38%. Results: 52.3% of patients (65.6% of macroadenomas, 33.3% of microadenomas) presented at least 1 pituitary deficiency: isolated deficiency in 29.8%, multiple deficiencies in 30% and panhypopituitarism in 9%. Isolated deficiencies were hypogonadism in 11.5% of patients (8% in micro-, 14% in macroadenomas), hypoadrenalism in 10.1% (14% in micro-, 7% in macroadenomas) and GHD in 8.3% (8.9% in micro-, 7.8% in macroadenomas). About 30% of microadenomas had at least 1 pituitary deficiency at diagnosis, independently of tumor localization within the sellar region. Conclusions: The presence of isolated hypoadrenalism suggests that the order of appearance of hypopituitarism does not always follow the one expected. Given the relatively high prevalence of isolated hypoadrenalism even in microadenomas, we suggest a full assessment of basal and dynamic pituitary function in all NFPA regardless of tumor size

Analysis of short- and long-term metabolic effects of growth hormone replacement therapy in adult patients with craniopharyngioma and non-functioning pituitary adenoma

Purpose: Adult patients operated for craniopharyngioma develop more frequently GH deficiency (GHD) than patients operated for non-functioning pituitary adenoma (NFPA). The aim of the study was to compare both short- (1 year) and long-term (5 years) effects of rhGH in 38 GHD adult patients (19 operated for Craniopharyngioma (CP) and 19 for NFPA). Methods: IGF-I levels, body composition (BF %), BMI, lipid profile and glucose homeostasis were evaluated in all patients. Pituitary MRI was performed at baseline and during follow-up, as needed. Results: At baseline no difference between the two groups was observed, apart from a higher prevalence of diabetes insipidus in CP patients (79 vs 21 %). After 12 months, IGF-I SDS normalized and BF % significantly decreased only in the NFPA group. During long-term treatment, decrease in BF % and improvement in lipid profile shown by reduction in total- and LDL-cholesterol were present in NFPA group only, while increase in insulin levels and HbA1c and decrease of QUICKI were observed in CP patients only. Accordingly, after long-term therapy, the prevalence of metabolic syndrome (MS) was significantly higher in CP than in NFPA group (37 % in CP and in 5 % in NFPA group; p < 0.05). Conclusion: The present data suggest that CP patients are less sensitive to the positive rhGH effects on lipid profile and BF % and more prone to insulin sensitivity worsening than NFPA patients, resulting in increased prevalence of MS in CP only

Screening for ACTH-dependent hypercortisolism in patients affected with pituitary incidentaloma

Context: Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage. Objective: The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs. Design, subjects, and methods: A total of 68 consecutive patients (48 females and 20 males, aged 18-82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively. Results: Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH. Conclusions: Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs

Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors

Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis

GH response to oral glucose tolerance test : a comparison between patients with acromegaly and other pituitary disorders

Context: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments. Objective: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT. Design, Subjects, and Methods: Thirty-three patients (24 females and nine males, aged 50.1 \ub1 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT. Results: In HPD patients mean postglucose nadir GH levels were 0.11 \ub1 0.08 \u3bcg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 \ub1 0.08 vs. 0.08 \ub1 0.08 \u3bcg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 \ub1 0.13 \u3bcg/liter, P = 0.02), although there was an overlapping in about half of patients. Conclusions: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function