Complete and sustained remission of hypercortisolism with pasireotide treatment of an adrenocorticotropic hormone (ACTH)-secreting thoracic neuroendocrine tumor: an n-of-1 trial.

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

Could Lipid Profile be Used as a Marker of Autonomous Cortisol Secretion in Patients with Adrenal Incidentalomas?

Adrenal incidentalomas (AIs) have been associated with an increased risk of metabolic syndrome and dyslipidemia, though evidence regarding the latter is limited. Lipid abnormalities in patients with AIs have been associated with subclinical hypercortisolism. The current study aims to test whether lipid profile in patients with AIs predicts "autonomous cortisol secretion" (ACS). Patients with AIs found on either computerized tomography (CT) or magnetic resonance imaging (MRI), were included in a prospective cohort study. All patients were followed up for at least three years. Alterations in their hormonal and lipid profiles were recorded. Ninety-four patients (69 women) harboring 111 AIs were included. There were no differences between patients with ACS and those without, with respect to their baseline lipid profile [total cholesterol, low-density-lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C] and blood pressure (systolic and diastolic). Non-HDL-C concentrations decreased over time (Repeated Measures ANOVA, p=0.013), despite patients' body mass index (BMI) remaining unchanged. Logistic regression analysis revealed that the only predictor of ACS was the size of AIs, as calculated by CT or MRI. The current study demonstrated that lipid profile at baseline or during follow-up cannot predict ACS in patients with AIs. However, larger AIs may have a greater probability of ACS.

Enduring remission of active and sight-threatening Graves' orbitopathy with rituximab: report of two cases.

Intravenous (i.v.) glucocorticosteroids (GCs) constitute the first-line treatment for active and moderate-to-severe Graves' orbitopathy (GO). In cases of persistent disease, rituximab, a monoclonal anti-CD20 antibody, may be used, although studies have yielded conflicting results. In case 1, a 50-year-old female heavy smoker presented with severe bilateral disfiguring eyelid edema of four months, bilateral exophthalmos and a clinical activity score (CAS) of 5/7. Laboratory investigation showed thyrotoxicosis and high thyroid-stimulating immunoglobulin (TSI) levels [32 IU/L (normal <1.75]. After minor improvement by i.v. methylprednisolone and standard retrobulbar radiotherapy (20 Gy), her visual acuity progressively declined to "hand motion". Rituximab was administered (two pulses of 500 mg, two weeks apart), with significant response. At 3 1/2 years of follow-up, CAS is 0/7 and CD20+ lymphocytes remain at the lower normal range. In case 2, a 78-year-old non-smoker male was referred for management of severe active GO, one month after total thyroidectomy for Graves' thyrotoxicosis (TSI: 6.74 IU/L). Over the preceding two-three months, severe GO manifested with chemosis, constant diplopia, loss of color vision and acuity of 1/10 bilaterally (CAS: 7/7). Following partial response to i.v. methylprednisolone and concomitant radiotherapy, rituximab (two pulses of 500 mg each, two weeks apart), was administered. Vision partially recovered and GO remains in remission one year later, even after 131I (100 mCi) administration for papillary thyroid carcinoma (TSI: 0.9 IU/L and CD20+ count at the lower normal range). In conclusion, rituximab may be an effective second-line therapy in GO patients, providing long-lasting remission.

Periostin and sclerostin levels in juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare, autosomal recessive disorder featuring markedly increased serum alkaline phosphatase activity, indicative of greatly accelerated bone turnover throughout the skeleton. The main aim of this study was to evaluate circulating periostin and sclerostin levels in two adult patients with mild JPD (due to "Balkan" mutation). We measured periostin and sclerostin levels in a previously described woman and a newly diagnosed man with JPD, and 10 apparently healthy individuals, matched (1:5) to JPD patients for gender, age and body mass index. Sclerostin levels were similar between JPD patients and controls. Periostin levels were about 2.5 times higher in JPD patients. Periostin and sclerostin levels were negatively correlated (rs= -0.63; p=0.03). In conclusion, a trend towards higher periostin levels was observed in JPD patients, whereas sclerostin levels were similar to controls.

Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study.

We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr-Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis.

Long term follow-up of patients with prolactinomas and outcome of dopamine agonist withdrawal: a single center experience.

Dopamine agonists (DA) are the mainstay of treatment for patients with prolactinomas. To describe the efficacy of treatment and the outcomes of DA withdrawal. Retrospective review of electronic medical records of patients with prolactinomas from 1985 to 2009. Seventy-nine patients (17 men/62 women), aged 35.3 ± 1.6 years at diagnosis were studied. The mean follow-up time was 84.7 ± 9.2 months (range 0-336). The mean initial size of microadenomas was 0.74 ± 0.10 cm (range 2.41 ± 0.39) and of macrodenomas 2.41 ± 0.39 cm (range 1.1-8) and serum prolactin (PRL) levels were 112 ± 19 and 263 ± 59 ng/ml, respectively (normal range 0-40). Fifty-one (65%) prolactinomas were micro- and 28 (35%) were macroadenomas. DA led to a decrease in adenoma size in 71% of them, while 53% of microadenomas were not visible during follow-up. In 26 patients, DA withdrawal was decided. After therapy of >24 months and a mean follow-up time of 49 ± 11 months (range 3-168), 15 subjects (58%) showed no recurrence of hyperprolactinemia. Higher remission rates, although not statistically significant, were observed with cabergoline (75%). The mean PRL levels before DA discontinuation were 12.2 ± 2.3 ng/ml (range 0.5-44.7) and after discontinuation they were significantly lower than pre-treatment values. Recurrence of hypeprolactinemia was evident during the first year in all but one patient. Remission rates were not associated with age or size of adenoma at diagnosis, initial or before DA discontinuation PRL levels and duration of treatment. DA withdrawal was followed by remission of hyperprolactinamia in about half of patients after >2 years of treatment.

A mutation in NOTCH2 gene first associated with Hajdu-Cheney syndrome in a Greek family: diversity in phenotype and response to treatment.

INTRODUCTION: Hajdu-Cheney Syndrome (HCS) is a rare genetic autosomal dominant disorder, characterized by distinctive facial features, acroosteolysis, and severe osteoporosis. Very rarely HCS is associated with polycystic kidney disease, splenomegaly or Crohn's disease (CD). It is caused by gain-of-function mutations in NOTCH2 gene. Treatment with bisphosphonates or denosumab is reported to result in BMD increase. OBJECTIVE: We report a mutation in exon 34 of NOTCH2 gene, in a Greek pedigree, with diverse phenotypes among members. DESCRIPTION OF THE PEDIGREE: The 48-year-old mother had a history of a T12 vertebral fracture, postpartum at the age of 21 and two subsequent uneventful full-term pregnancies and never received treatment. Her 29-year-old son, presented with severe osteoporosis and multiple morphological vertebral fractures. Her 21-year-old daughter had recurrent vertebral fractures starting at 10 years of age. At 17 years, she developed severe CD, resistant to treatment with biologic agents, and functional hypothalamic hypogonadism. One male pedigree died of cystic fibrosis. All subjects bore the typical facial characteristics and acroosteolysis, while none had splenomegaly or renal defects. Zoledronate infusion led to BMD increase. GENETIC TESTING: Mutation in c.6758 G > A (NM_008163.1), leading to a Trp2253Ter replacement. This mutation has been reported as possibly pathogenic (SCV000620308), but not in association with HCS. CONCLUSIONS: Bone involvement can present with diverse severity in the same pedigree, ranging from low BMD to multiple fragility fractures. Antiresorptive therapy improves BMD, but its anti-fracture efficacy remains to be shown. The presence of CD might indicate the significant role of NOTCH2 signaling in different tissues.

Profound hypocalcemia following effective response to zoledronic acid treatment in a patient with juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare, autosomal recessive osteopathy. Although it has phenotypic overlap with Paget's disease of bone (PDB), it is probably a distinct entity. Because of its rarity, optimal disease management has not yet been established by randomized controlled trials. However, clinical, biochemical, and radiographic improvement has been reported after treatment with antiresorptive agents, including calcitonin and bisphosphonates (BPs). Compared with other BPs, zoledronic acid (ZOL) has a higher affinity to bone mineral and is a stronger inhibitor of the enzyme farnesyl pyrophosphate synthase (the main target of nitrogen-containing BPs), properties that explain the prolonged effect of ZOL on bone turnover and render it a therapeutic option for JPD, similar to PDB. We describe hereby, for the first time in the literature, the case of a patient with JPD who developed severe hypocalcemia and secondary hyperparathyroidism following effective treatment with ZOL.

Serum homocysteine, folate and vitamin B12 in patients with Paget's disease of bone: the effect of zoledronic acid.

High serum homocysteine (HCY) and indirectly deficiency of folate and/or vitamin B(12) stimulate bone resorption and adversely affect collagen cross-linking. The aim of this study was the evaluation of serum levels of HCY, folate and vitamin B(12) in patients with Paget's disease of bone (PDB) and the effect of zoledronic acid (ZOL) on their serum levels. Nine consecutive patients with polyostotic PDB (median age 66 years) received a single 5-mg ZOL infusion. Blood samples for HCY, folate, vitamin B(12), 25-hydroxyvitamin D (25-OH-D), total serum alkaline phosphatase (TSAP), bone-specific serum alkaline phosphatase (BSAP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were obtained at baseline and 3, 6 and 12 months after ZOL infusion. Twelve age-, gender- and BMI-matched healthy individuals were recruited for the control group at baseline assessment. Patients with PDB had significantly higher serum HCY (p = 0.028), folate (p < 0.001) and bone markers [TSAP (p < 0.001), BSAP (p < 0.001) and CTX (p < 0.001)] compared with the control group at baseline. In the pagetic group, serum HCY significantly decreased 3 months after ZOL infusion and remained essentially unchanged up to the end of the study (p = 0.005). Serum vitamin B(12) and folate remained unaffected throughout the study. Our data suggest that serum HCY levels are increased in patients with PDB. A single ZOL infusion results in a decrease in HCY levels that might represent another mechanism for the reduction of the activity of PDB achieved by ZOL.

Dual-energy X-ray absorptiometry and quantitative ultrasound in patients with Paget's disease of bone before and after treatment with zoledronic acid: association with serum bone markers and Dickkopf-1.

The main aim of this study was to determine the effect of zoledronic acid (ZOL) on parameters of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in unaffected bones of patients with Paget's disease of bone (PDB). The secondary aim was the association of bone markers and Dickkopf (DKK)-1 with parameters of DXA and QUS. Ten consecutive patients with polyostotic PDB (median age: 63 yr) received a single 5-mg ZOL infusion. The patients were subjected to calcaneal QUS and DXA of both lumbar spine (LS) and femoral neck (FN). Blood samples for serum bone markers and DKK-1 were serially obtained for 12 mo. There was a significant increase in LS (p=0.005) and FN bone mineral density (BMD) (p=0.021) 12 mo after ZOL infusion. QUS parameters remained unaffected throughout the study. A significant correlation between broadband ultrasound attenuation and DKK-1 (p<0.001) and between speed of sound and DKK-1 (p=0.033) at baseline was found, which remained significant after adjustment for gender, age, and body mass index. Our data suggest that a single ZOL infusion significantly increases nonpagetic BMD 12 mo after treatment but has no effect on QUS parameters or DKK-1. Significant correlations were observed between QUS parameters and DKK-1 at baseline.

Pituitary Dysfunction as a Cause of Cardiovascular Disease.

The hypothalamic-pituitary axis is responsible for the neuroendocrine control of several organ systems. The anterior pituitary directly affects the functions of the thyroid gland, the adrenal glands, and gonads, and regulates growth and milk production. The posterior hypophysis, through nerve connections with the hypothalamic nuclei, releases vasopressin and oxytocin responsible for water balance and social bonding, sexual reproduction and childbirth, respectively. Pituitary gland hormonal excess or deficiency results in dysregulation of metabolic pathways and mechanisms that are important for the homeostasis of the organism and are associated with increased morbidity and mortality. Cardiovascular (CV) disorders are common in pituitary disease and have a significant impact on survival. Hormonal imbalance is associated with CV complications either through direct effects on the heart structure and function and vasculature or indirectly by altering the metabolic profile. Optimal endocrine control can prevent or reverse CV defects and preserve survival and quality of life. In this review, we discuss the effects of pituitary hormone excess and deficiency on the CV system. Specifically, we assess the impact of Somatotroph, Corticotroph, Gonadotroph, and Lactotroph anterior pituitary axes on the CV system. The effect of posterior pituitary function on the CV system is also explored.

Correction to: A mutation in NOTCH2 gene first associated with Hajdu-Cheney syndrome in a Greek family: diversity in phenotype and response to treatment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). There is currently no approved treatment for NAFLD. The main aim was the evaluation of the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) vs. dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment on noninvasive indices of hepatic steatosis and fibrosis in patients with T2DM. METHODS: In this retrospective study, three noninvasive indices of hepatic steatosis [HSI, NAFLD ridge score, and triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio] and five of fibrosis (APRI, FIB-4, NAFLD fibrosis score, BAAT and BARD) were calculated before and after (6-18 months) the addition of a DPP-4i (n = 152) or a GLP-1 RA (n = 37) in patients with T2DM. RESULTS: Regarding steatosis indices, NAFLD ridge score was significantly decreased in the GLP-1 RA group (baseline: 0.90 ± 0.34, follow-up: 0.67 ± 0.24; p = 0.001), but not in the DPP-4i group (p = 0.25); the difference for group∗time interaction was significant (p = 0.02). HSI showed a trend between groups, being significantly different at baseline and follow-up (p < 0.001) with no significant difference in group∗time interaction. Indices of fibrosis were not essentially changed within or between groups. CONCLUSIONS: NAFLD ridge score was significantly decreased after the addition of GLP-1 RA in patients with T2DM. This study warrants further prospective clinical trials.

No difference between strontium ranelate (SR) and calcium/vitamin D on bone turnover markers in women with established osteoporosis previously treated with teriparatide: a randomized controlled trial.

UNLABELLED: Objective To evaluate the effect of strontium ranelate (SR) on bone turnover markers in women with established osteoporosis previously treated with teriparatide (TPTD--recombinant human PTH 1-34). DESIGN PATIENTS: Twenty-two postmenopausal Caucasian women (aged 65.7 +/- 1.7 years) with established osteoporosis previously treated with TPTD 20 microg daily for 18 months were randomly assigned to receive either SR (SR group, n = 11) or calcium and vitamin D (control group, n = 11). MEASUREMENTS: Blood samples for serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx) and total alkaline phosphatase (ALP) were obtained from all women before (pre-TPTD) and after (post-TPTD) TPTD administration, as well as 6 months after SR or calcium/vitamin D administration (post-SR/Ca). RESULTS: Serum P1NP, CTx and total ALP increased significantly after TPTD treatment and decreased at the end of the study in both SR and control groups, with no difference between them. CONCLUSIONS: SR following TPTD administration acts predominantly as an antiresorptive agent with no evidence of additional osteoanabolic action. In this setting, SR is not more effective than Ca/vitamin D as far as bone turnover markers are concerned.

Coexistence of a large functioning parathyroid cyst with papillary thyroid carcinoma: A case report and review of the literature.

Parathyroid cysts constitute a rare cause of primary hyperparathyroidism (PHPT). PHPT may also rarely coexist with non-medullary thyroid carcinoma (NMTC). We describe a case of a 70-year-old woman who was diagnosed with PHPT, on the occasion of nephrolithiasis (corrected calcium and PTH levels: 10.8 mg/dl and 187 pg/ml, respectively). Ultrasonographic and scintigraphic investigation confirmed the diagnosis of a large parathyroid cyst attached to the lower pole of the right thyroid lobe and, consequently, the patient underwent parathyroidectomy. Due to the coexistence of multinodular goitre, with some nodules characterized as suspicious of malignancy, a total thyroidectomy was also performed. A histological diagnosis of cystic parathyroid adenoma was made. A unifocal papillary thyroid carcinoma of follicular subtype, 6 mm in diameter, was also detected. The patient's post-surgical course was uneventful and she remained normocalcaemic two years later. PHPT may rarely coexist with papillary thyroid carcinoma (PTC). The pathogenetic mechanisms linking these two endocrine entities are currently unknown.

Association between vitamin D receptor gene polymorphisms and Graves' disease: a systematic review and meta-analysis.

PURPOSE: The pathogenesis of Graves' disease (GD) and orbitopathy (GO) is not completely elucidated. On the other hand, vitamin D receptor (VDR) gene polymorphisms have been associated with vulnerability to a plethora of chronic autoimmune diseases. The primary aim of this study was to synthesize evidence on the association between VDR gene polymorphisms and GD. Secondary aim was to investigate their association with GO. METHODS: A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to December 8, 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). Heterogeneity was quantified with I2 index. RESULTS: Ten studies were included in the qualitative and quantitative analysis. TT subtype of TaqI polymorphism was associated with an increased risk of GD compared with Tt and tt polymorphisms (OR: 1.42; 95% CI, 1.05-1.94, p = 0.025), whereas tt was associated with a lower risk of GD, compared with TT and Tt polymorphisms (OR: 0.79; 95% CI, 0.62-0.99, p = 0.043). No association was found for ApaI, BsmI, and FokI polymorphisms. The bb subtype of BsmI polymorphism was associated with a lower risk in Asian, but with a higher GD risk in Caucasian populations, compared with BB/Bb subtypes. No eligible study was found regarding the association between VDR gene polymorphisms and the risk of GO. CONCLUSIONS: The TT subtype of the TaqI polymorphism was associated with a higher susceptibility for GD compared with Tt and tt. Regarding BsmI, the bb subtype was associated with increased GD risk in Caucasians, whereas it is protective in Asians.

Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly.

OBJECTIVE: Complete remission of acromegaly is associated with favourable changes in cardiovascular risk parameters. We evaluated the effects of suboptimal therapy on haemodynamic, metabolic, inflammatory and coagulation cardiovascular risk indices. DESIGN AND METHODS: Eighteen acromegalic patients on somatostatin analogues, with incomplete biochemical control, were evaluated at diagnosis and 6 months after treatment and compared to 15 healthy age- and body mass index (BMI)-matched controls. Measurements of blood pressure, GH, IGF-I, glucose, insulin, glycated haemoglobin (HbA1c), lipids, apolipoprotein A1 (apoA1), apoB, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA) and circulating thrombomodulin were performed in all study participants, followed by an oral glucose tolerance test (OGTT). Insulin sensitivity (IS) was expressed by the Matsuda index (OGTT(ISI)). RESULTS: Partial control of acromegaly resulted in a significant reduction in systolic and diastolic blood pressure, glucose, insulin, HbA1c, total (T-C) and low density lipoprotein cholesterol (LDL-C) and triglyceride levels, and a significant increase in apoA1, high density lipoprotein cholesterol (HDL-C) and OGTT(ISI) compared to pretreatment levels. Plasma fibrinogen and PAI-1 levels fell significantly [respectively (mean +/- SEM), 11.04 +/- 0.41 vs. 10.12 +/- 0.34 micromol/l, P = 0.003 and 9.6 +/- 1.97 vs. 6.55 +/- 1.89 microg/l, P < 0.001]. However, a marked reduction in tPA [median (IQR) 5.1 (2.5-15) vs. 3.4 (2.4-8.6) microg/l, P = 0.031] and an increase in hs-CRP [median (IQR) 0.05 (0.03-0.11) vs. 0.1 (0.06-0.23) mg/l, P < 0.001] were also noted. On treatment, acromegalic patients were comparable to controls, except for OGTT(ISI), lipoprotein(a) [Lp(a)], fibrinogen and tPA and HDL-C levels. Thrombomodulin and apoB levels were not affected by treatment. CONCLUSIONS: Partial control in disease activity following somatostatin analogues results in significant improvement in a considerable number of cardiovascular risk markers in acromegaly.

Serum thyrotropin concentration as a biochemical predictor of thyroid malignancy in patients presenting with thyroid nodules.

PURPOSE: Serum thyrotropin (TSH) is a well-established growth factor for thyroid nodules and suppression of TSH concentrations by administering exogenous thyroxine may interfere with the growth of established nodules as well as the formation of new thyroid nodules. The aim of this study was to investigate whether serum TSH at presentation is a predictor of thyroid malignancy in patients with thyroid nodules. METHODS: A total of 565 patients without overt thyroid dysfunction, who presented with palpable thyroid nodule(s) between 1988 and 2004 and underwent at least one fine-needle aspiration biopsy, were retrospectively evaluated. RESULTS: The final diagnostic outcome was established after surgery (n = 122) or after a minimum of 1-year clinical follow-up period. Higher rates of malignancy were observed in patients with serum TSH in the upper tertile of the normal range (P = 0.026). Binary logistic regression analysis revealed significantly increased adjusted odds ratios for the diagnosis of malignancy in patients with serum TSH 1.5-4.0 mIU/l when compared to those with either TSH 0.4-0.8 mIU/l (P = 0.005) or TSH 0.9-1.4 mIU/l (P = 0.007). CONCLUSIONS: The risk of malignancy in thyroid nodules increases in parallel with TSH concentrations within the normal range. TSH concentration at presentation is an independent predictor of thyroid malignancy.