Idiopathic central diabetes insipidus in a large cohort of patients: the hypopituitarism ENEA rare observational (HEROS) study.

Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries. The cohort included 92 patients (59 females 64%), mean age at diagnosis was 35.4 ± 20.7 years, and a mean follow up of 19.1 ± 13.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40(48%) had normal sellar imaging, and 43(52%) had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 (6.5%) patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient. Patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up.

Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. PURPOSE: RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. METHODS: A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. RESULTS: We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value. CONCLUSION: Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.

Outcome of pregnancies in a large cohort of women with acromegaly.

OBJECTIVE: To assess the outcome of pregnancies in a large cohort of women with acromegaly. DESIGN AND METHODS: This is a retrospective analysis of 31 pregnancies in 20 patients with acromegaly. RESULTS: Twenty-seven pregnancies resulted in healthy offspring, and 4 resulted in abortion. Three patients underwent transsphenoidal surgery during pregnancy. IGF-1 levels remained elevated during pregnancy in 4 pregnancies and normalized in 23 cases. Fifteen cases were followed during pregnancy without any medical or surgical treatment, and 13 of these exhibited normal IGF-1 levels. Before or during pregnancy, somatostatin receptor ligands usage was not associated with higher risk for adverse outcomes. Arterial hypertension worsening (45%) and impairment of glucose levels (32%) were the most common complications during pregnancies. There were no maternal or neonatal deaths. One woman delivered twins. Two cases of congenital malformations and one with foetal macrosomia were observed. Caesarean delivery was performed in sixteen cases. CONCLUSION: Our study confirms the impact of gestation on IGF-1 levels. However, it also indicates that acromegaly still holds an increased risk for worsening of comorbidities, especially in uncontrolled patients.

A primer on the genetics of medullary thyroid cancer.

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%-5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation; 43%-65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype-phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma-paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease. In this narrative review, we focus on RET proto-oncogene physiology and pathogenesis induced by germline and somatic RET mutations, the genotype-phenotype correlation, and the management and follow-up of patients with germline-mutated medullary thyroid cancer.

High blood glucose variability is associated with bacteremia and mortality in patients hospitalized with acute infection.

BACKGROUND: Limited data are available regarding the association between glucose levels variability (GV) and outcomes of patients hospitalized with acute infectious diseases. AIM: To determine the association between GV and bacteremia, length of stay (LOS) and mortality. METHODS: A retrospective study of patients hospitalized in departments of medicine with respiratory tract, urinary tract and skin and soft tissue infections during 2011-17. GV was assessed by the coefficient of variation (CV) of glucose levels during hospitalization and was divided into tertiles (CV ≤ 16%, 17-29%, >29%). LOS, bacteremia rates and all-cause mortality (30 days, 90 days and after 5 years) were evaluated for the patients with and without DM according the three GV categories. RESULTS: The study consisted of 1485 patients, 838 (56%) were diabetic. There was no significant association between GV and LOS. Bacteremia rates were higher in the upper GV tertile compared with the lower one (6% vs. 2%, P = 0.007). Mid and upper tertiles compared with the lower one were significantly associated with increased 30-day mortality (13% vs. 5%, P = 0.005; and 40% vs. 5%, P = 0.002, respectively). A decreased 5 years survival was observed for both diabetic and non-diabetic patients in the mid and upper GV tertiles [adjusted HRs 0.8 (95% CI, 0.6-1.04) and 0.6 (95% CI, 0.5-0.9) in diabetic patients and 0.7 (95% CI, 0.5-0.9) and 0.5 (95% CI, 0.3-0.7) in the non-diabetic ones]. CONCLUSION: In diabetic and non-diabetic patients, hospitalized in non-ICU setting with acute infectious diseases, increased GV is associated with increased risk of bacteremia, short and long-term mortality.

[The inflow of the substrate can regulate the persistence of memory of enzymes having the properties of hysteresis: theoretical analysis].

A simple kinetic model of hysteretic enzymes with the influx of substrate or ion (transported by the enzyme) is considered. Two alternative steady activity levels are shown to arise in the system with a hysteretic enzyme. The transition between these levels can proceed in an oscillatory manner. The duration of the initial steady activity level is shown to be determined by the initial substrate (or ion) level, and the oscillatory transition between the activity levels is the property of hysteretic enzymes. It was shown for plasma membrane Ca2+-ATPase as an example that the level of the signal can be encoded into the time interval in which the enzyme retains the memory about this signal.