Central diabetes insipidus: beware of Langerhans cell histiocytosis!

Langerhans cell histiocytosis (LCH) is a rare disorder, characterised by a monoclonal proliferation of aberrant histiocytes that accumulate in and infiltrate into different organs. When the hypothalamic-pituitary axis is involved, central diabetes insipidus (CDI) can be its first manifestation. Three cases of LCH with central diabetes insipidus were retrospectively analyzed: Case 1 is a 41-year old female presenting with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary showed hypophysitis. Subsequently, she developed bone lesions and a biopsy demonstrated LCH. Case 2 is a 51-year old female presenting in 2009 with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary revealed hypophysitis. LCH was suspected because of known pulmonary histiocytosis. Coexisting bone lesions were biopsied and confirmed LCH. Case 3 is a 44-year old female presenting with diabetes insipidus. She was treated with desmopressin as well. MRI of the pituitary gland showed impressive thickening of the infundibulum. A few months later, she developed skin lesions and a biopsy revealed LCH. Conclusively, LCH is a rare, elusive and probably underdiagnosed disease with a broad disease spectrum. Due to infiltration of the hypothalamic-pituitary axis, CDI can be the first manifestation, even before LCH is diagnosed. Therefore, LCH should be considered in the diagnostic workup of CDI.

A new mutation in the calcium-sensing receptor gene causing hypocalcaemia: case report of a father and two sons.

BACKGROUND: Regulation of calcium is mediated by parathyroid hormone (PTH) and 1.25-dihydroxyvitamine D3. The calcium-sensing receptor (CaSR) regulates PTH release by a negative feedback system. Gain-of-function mutations in the CaSR gene reset the calcium-PTH axis, leading to hypocalcaemia. PATIENTS AND METHODS: We analysed a family with hypocalcaemia. The proband was a 47-year-old man (index, patient I1), who presented with paraesthesias in both limbs. He has two sons (patient II1 a nd I I2). The probands' lab results showed: serum calcium of 1.95 mmol/l, albumin 41 g/l, phosphate 0.81 mmol/l and PTH 6.6 ng/l (normal 15-65 ng/l). Based on this analysis, we suspected a hereditary form of hypocalcaemia and performed genetic testing by polymerase chain reaction and Sanger sequencing of the coding regions and intron boundaries of the CaSR gene. Genetic analysis revealed a new heterozygous mutation: c.2195A>G, p.(Asn732Ser) in exon 7. The lab results of patient II1 showed: serum calcium of 1.93 mmol/l, phosphate 1.31 mmol/l, albumin 41 g/l, and PTH 24.3 ng/l. His genotype revealed the same activating mutation and, like his father, he also lost his scalp hair at an early adolescent age. Patient II2 is asymptomatic, and has neither biochemical abnormalities, nor the familial CaSR gene mutation. He still has all his scalp hair. CONCLUSIONS: 1) The c.2195A>G, p.(Asn732Ser) mutation in exon 7 of the CaSR gene leads to hypocalcaemia, and has not been reported before in the medical literature. 2) Possibly, this mutation is linked to premature baldness.

Impact of thyroid autoimmunity in euthyroid women on live birth rate after IUI.

Study question: Does thyroid autoimmunity (TAI) predict live birth rate in euthyroid women after one treatment cycle in IUI patients? Summary answer: TAI as such does not influence pregnancy outcome after IUI treatment. What is known already: The role of TAI on pregnancy outcome in the case of IVF/ICSI is largely debated in the literature. This is the first study to address this issue in the case of IUI. Study design, size, duration: This was a retrospective cohort study. A two-armed study design was performed: patients anti-thyroid peroxidase (TPO)+ and patients anti-TPO-. All patients who started their first IUI cycle in our fertility center between 1 January 2010 and 31 December 2014 were included. After exclusion of those patients with or being treated for thyroid dysfunction, 3143 patients were finally included in the study. Participants/materials, setting, methods: After approval by the institutional review board we retrospectively included all patients who started their first IUI cycle in our center between 1 January 2010 and 31 December 2014 with follow-up of outcome until 31 December 2015. Patients with clinical thyroid dysfunction were excluded (thyroid-stimulating hormone (TSH) <0.01 mIU/l; TSH >5 mIU/l) as were patients under treatment with levothyroxine or anti-thyroid drugs. These patients were then divided into two main groups: patients anti-TPO+ and patients anti-TPO- (= control group). Live birth delivery after 25 weeks of gestation was taken as the primary endpoint of our study. As a secondary endpoint, we evaluated differences in live birth delivery after IUI according to different upper limits of preconception TSH thresholds (<2.5 and <5.0 mIU/l). Furthermore, the influence of thyroid function (TSH, free thyroxine (fT4)), anti-TPO status, age, smoking, BMI, parity, ovarian reserve (anti-mullerian hormone (AMH) and FSH), IUI indication and IUI stimulation on live birth rate was analyzed. Main results and the role of chance: Between-group comparison did not show any significant difference between the anti-TPO+ and anti-TPO- group with respect to live birth delivery-, pregnancy- or miscarriage rate with odds ratio at 1.04 (95% CI: 0.63; 1.69), 0.98 (95% CI: 0.62; 1.55) and 0.74 (95% CI: 0.23; 2.39), respectively. In addition, there were no significant differences in live birth delivery-, pregnancy- or miscarriage rate when comparing subgroups according to TSH level (TSH ≥2.5 mIU/l vs. TSH <2.5 mIU/l) with an odds ratio at 1.05 (95% CI: 0.76; 1.47), 1.04 (95% CI: 0.77; 1.41) and  0.95 (95% CI: 0.47; 1.94), respectively. Limitations, reasons for caution: This study was powered for the primary aim, live birth rate. The limitations of this study are the absence of region-specific reference ranges for thyroid hormones and the absence of follow-up of TSH values during ART and subsequent pregnancy. Moreover, there was a time difference of 5 months between thyroid assessment and the start of stimulation. The area where the study was conducted corresponds to a mild iodine deficient area and data should be translated with caution to areas with different iodine backgrounds. Wider implications of the findings: Our findings indicate comparable pregnancy-, abortion- and delivery rates in women with and without TAI undergoing IUI. Moreover, we were unable to confirm a negative effect of TSH level above 2.5 mIU/l on live birth delivery rate. We therefore believe that advocating Levothyroxine treatment at TSH levels between 2.5 and 4 mIU/l needs to be considered with caution and requires further analysis in a prospective cohort study. Study funding/competing interest(s): No external funding was used for this study. No conflicts of interest are declared.

Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs.

BACKGROUND Previous meta-analyses of observational data indicate that pregnant women with subclinical hypothyroidism have an increased risk of adverse pregnancy outcome. Potential benefits of levothyroxine (LT4) supplementation remain unclear, and no systematic review or meta-analysis of trial findings is available in a setting of assisted reproduction technologies (ART). METHODS Relevant trials published until August 2012 were identified by searching MEDLINE, EMBASE, Web of Knowledge, the Cochrane Controlled Trials Register databases and bibliographies of retrieved publications without language restrictions. RESULTS From 630 articles retrieved, we included three trials with data on 220 patients. One of these three trials stated 'live delivery' as outcome. LT4 treatment resulted in a significantly higher delivery rate, with a pooled relative risk (RR) of 2.76 (95% confidence limits 1.20-6.44; P = 0.018; I(2) = 70%), a pooled absolute risk difference (ARD) of 36.3% (3.5-69.0%: P = 0.030) and a summary number needed to treat (NNT) of 3 (1-28) in favour of LT4 supplementation. LT4 treatment significantly lowered miscarriage rate with a pooled RR of 0.45 (0.24-0.82; P = 0.010; I(2) = 26%), a pooled ARD of -31.3% (-48.2 to -14.5%: P < 0.001) and a summary NNT of 3 (2-7) in favour of LT4 supplementation. LT4 treatment had no effect on clinical pregnancy (RR 1.75; 0.90-3.38; P = 0.098; I(2) = 82%). In an ART setting, no data are available on the effects of LT4 supplementation on premature delivery, arterial hypertension, placental abruption or pre-eclampsia. CONCLUSIONS Our meta-analyses provide evidence that LT4 supplementation should be recommended to improve clinical pregnancy outcome in women with subclinical hypothyroidism and/or thyroid autoimmunity undergoing ART. Further research is needed to determine pregnancy outcome after close monitoring of thyroid function to maintain thyroid-stimulating hormone and free T4 levels within the trimester-specific reference ranges for pregnancy.

Cushing's disease: diagnosis through the nose. A case report.

In Cushing's disease clinical symptoms are usually related to the ACTH hypersecretion. On diagnosis these secreting tumours tend to be small due to their ability to reach clinical detection early. However, symptoms may also be caused by mass-related effects such as the depression of secretion of other pituitary hormones. Furthermore growth related symptoms may occur due to the invasion of the suprasellar region with compression of the visual system. As we illustrate in a case report, when spreading of pituitary adenoma occurs to the infrasellar region, Cushing disease may manifest itself by rather atypical initial symptoms that are more related to ear-nose-throat (ENT) complaints. In these invasive macro adenomas multimodal therapy is usually required to achieve control of hypersecretion and mass related symptoms.

Systemic anaplastic large cell lymphoma presenting with cutaneous manifestations in a young man: a case report.

Skin lesions can be a sign of internal disease. When they are associated with persisting systemic signs, the possibility of an internal malignancy should always be considered. We describe a 25-year-old man who presented with weight loss, fatigue, subpyrexia, xerostomia and skin rash of 6 months duration. Physical examination showed a dry red skin, most prominent in the face, the palms of the hands and the soles of the feet. Laboratory investigations revealed signs of inflammation and a high level of antinuclear antibodies. Retroperitoneal lymph nodes were visualized on a CT scan of the abdomen. CT-guided biopsy of an abdominal lymph node revealed the presence of an anaplastic large cell lymphoma (ALCL), ALK-positive. A biopsy of the skin showed non-specific signs of inflammation.The patient underwent 8 cycles of chemotherapy according to the CHOP protocol. A complete remission was obtained. Non-Hodgkin lymphoma can indeed be associated with skin lesions. They result from direct invasion by malignant cells or are of paraneoplastic origin, as was the case in this patient.

Occurrence of pulmonary artery aneurysms and pulmonary artery thrombosis in a young man.

Behçet's disease (BD) is a multisystemic inflammatory disorder of unknown aetiology. Arterial involvement is uncommon but associated with important morbidity and mortality. We describe the clinical course of BD with severe pulmonary artery involvement in a 19-year-old man. He presented with massive haemoptysis related to pulmonary artery aneurysms. Initial treatment consisted in urgent right inferior lobectomy, corticosteroids and monthly intravenous cyclophosphamide. Subsequently, he developed pulmonary artery thrombosis at non-aneurysmatic sites. Corticosteroid therapy was intensified, monthly intravenous cyclophosphamide was continued and an anticoagulant was added to the treatment with a favourable clinical and radiological response. Our case illustrates that timely initiation of highly potent immunosuppressive therapy is critical to obtain a favourable outcome. At present, a consensus regarding optimal management of vascular BD is lacking. ALthough anticoagulation is not generally recommended, our report encourages a patient-based decision after carefully tailoring potential risks and benefits.

[Place of fibrates for the treatment of patients with atherogenic dyslipidemia]. / Place des fibrates dans le traitement de patients avec une dyslipidémie athérogène.

The demography of dyslipidemia has changed towards a more complex atherogenic dyslipidemia involving increased levels of LDL cholesterol, in particular highly atherogenic small dense particles, hypertriglyceridemia and low HDL cholesterol, together with increased levels of markers of inflammation, thrombogenesis and endothelial dysfunction. Statins were shown to significantly lower cardiovascular morbidity and mortality, but treated patients are still left with a high residual risk, in particular for those with metabolic syndrome, type 2 diabetes, or low HDL cholesterol levels. Fibrates have been shown to reduce plasma triglycerides and increase HDL cholesterol, while improving inflammation, thrombogenesis and endothelial dysfunction. Clinical trials with fibrates have demonstrated their potential to reduce cardiovascular morbidity and mortality too, often through other mechanisms than those of statins. Combination trials of statins with fibrates have shown a more complete improvement of lipid profile and risk markers than each class separately. In contrast with gemfibrozil, fenofibrate does not interact significantly with the pharmacokinetics of statins, and its combination with statins has been shown to have a low risk of muscular side-effects or liver toxicity. The ACCORD outcome trial is exploring possible benefits of the combination of fenofibrate with statins on morbidity and mortality of patients with type 2 diabetes.

Identifying non-alcoholic fatty liver disease among asymptomatic overweight and obese individuals by clinical and biochemical characteristics.

OBJECTIVE: To determine the prevalence of liver steatosis among asymptomatic individuals attending an out-patient clinic for a problem of overweight, and to define the discriminatory value of several characteristics for predicting liver steatosis among them. DESIGN AND PARTICIPANTS: Consecutive patients Swith a body mass index (BMI) of > or =25 kg/m2 who consented to undergo liver ultrasound and blood tests were recruited for inclusion. Receiver operating characteristic (ROC) curves were generated and statistical indices of diagnostic performance and their corresponding 95% confidence intervals (95% CI) were computed. Logistic regression analyses were performed to determine whether a combination of characteristics could improve diagnostic accuracy. RESULTS: We enrolled sixty-eight subjects (mean BMI, 37.5 kg/m2), of whom 39 (57.4%) had liver steatosis on ultrasound. Logistic regression analyses indicated that only 3 variables were significantly and independently correlated with liver steatosis: female gender, low adiponectin levels, and high insulin resistance index. A composite index for predicting liver steatosis was calculated by summing the risk factors of female gender, low adiponectin, and insulin resistance index (FAIR score). The accuracy of this score was determined by ROC analysis to be 0.85 (95% CI, 0.74-0.96; P < 0.001). The presence of two or more risk factors (FAIR score > or =2) had a sensitivity, specificity, positive predictive value, and negative predictive value of 77%, 91%, 92%, and 74%, respectively. The likelihood ratio for a positive result was 8.43. CONCLUSIONS: Among asymptomatic overweight individuals attending an out-patient clinic, the prevalence of liver steatosis on ultrasound is 57%. Female gender, the insulin resistance index, and low adiponectin are significant and independent predictors of liver steatosis. A combination of these three factors allows sensitivity and specificity for non alcoholic fatty liver of 77% and 91%, respectively.

Men with atherosclerotic stenosis of the carotid artery have lower testosterone levels compared with controls.

AIM: There is evidence to suggest an inverse association between serum levels of testosterone and coronary heart disease. The aim of this study was to compare endogenous sex hormone levels of men with severe internal carotid artery (ICA) atherosclerosis with age-matched controls. METHODS: Metabolic parameters and sex hormones were measured or calculated in 124 male patients undergoing carotid endarterectomy for high grade ICA stenosis and in 124 age-matched male controls. The presence or absence of atherosclerotic stenosis of ICA was determined by high resolution B-mode ultrasound. RESULTS: The cases had statistically significant lower levels of total testosterone (TT) (medians: 3.8 microg/L versus 4.3 microg/L, P=0.005) and sex hormone binding globulin (SHBG) (means: 39.8+/-17.2 versus 54.3+/-34.3 nmol/L, P<0.001) compared to controls. Multivariate linear regression analysis, adjusted for all clinical and physiologic parameters, showed a significant inverse association between ICA stenosis and TT (b=-0.158, P=0.013) and SHBG (beta=-0.259, P<0.001). CONCLUSION: This study provides evidence of a positive association between low serum androgen levels and severe ICA atherosclerosis in men. It suggests that higher, but physiological, levels of androgens could have a protective role in the development of atherosclerosis.

Respiratory consequences of obesity--an overview.

At the beginning of the 21st century obesity has become the leading chronic disease in the world. It is a major cause of morbidity mainly in the metabolic and cardiovascular areas. Moreover, it has progressively emerged as an important risk factor for respiratory diseases, a field that is often neglected. In this article, we reviewed the current understanding of the influence of obesity in adulthood on respiratory function, obstructive sleep apnoea-hypopnoea, obesity hypoventilation syndrome and asthma.

Hypophosphatemia and refeeding: a corrective or a preventive attitude?

Hypophosphatemia is a rare but potentially lethal complication of the refeeding of cachectic patients. Up until now a careful monitoring of the serum phosphor level was recommended and the deficit was corrected as needed. Illustrated by two case reports we propose the use of a preventive schedule in patients with a normal renal function. We show that preventively treated patients do not develop hypophosphatemia and thereby avoid serious complications such as sudden death. In the presence of normal kidney function we propose to administer phosphor at 2 x 10 mmol/day orally or between 10 and 30 mmol IV depending on the initial phosphor levels. Further treatment is then adapted to measured levels. In the presence of kidney malfunction we propose to keep the corrective schedule.

Is systematic screening for thyroid disorders indicated in subfertile men?

CONTEXT: Data on the prevalence of thyroid disorders in male subfertility remain scarce. OBJECTIVE: To investigate the prevalence of thyroid dysfunction and thyroid autoimmunity in men with normal and abnormal semen characteristics. SETTING: Tertiary referral center for reproductive medicine of the University Hospital AZ-VUB, Brussels, Belgium. PATIENTS AND DESIGN: Two hundred and ninety-two men were stratified according to the presence of normal (group 1; n = 39) or abnormal (group 2; n = 253) semen characteristics. Thyroid function was assessed by serum thyrotropin (TSH) and free thyroxine (FT4), and thyroid peroxidase antibodies (TPO-Ab) for thyroid autoimmunity (TAI or TPO-Ab > 34 kU/l); both were correlated with semen characteristics. MAIN OUTCOME MEASURES: Semen characteristics were determined by World Health Organisation criteria (rapid + slow motility > or = 50% and concentration > or = 20 x 10(6)) and Kruger criteria (morphology > or = 14% normal cells). RESULTS: In group 1, the mean (+/- s.d.) age was 33 +/- 4 years; serum TSH was 1.6 (0.3-29.6) mU/l (median (range)) and FT4 was 12.2 (8.8-15.6) ng/l. In group 2, the mean age was 33 +/- 5 years, serum TSH was 1.3 (0.3-5.2) mU/l and FT4 was 12.5 (8.4-17.5) ng/l; (compared with group 1 P = 0.008 for TSH and P = 0.037 for FT4). In both groups, one patient had increased TSH (2.6% and 0.4%; P = not significant (ns)). In group 1, one patient had TAI and in group 2 twelve patients had TAI (2.6% compared with 4.7%; P = ns). FT4 was an independent determinant for semen characteristics. CONCLUSIONS: The prevalence of thyroid dysfunction and autoimmunity is comparable between men with normal and abnormal semen characteristics. On the basis of these data, we do not advise systematic screening for thyroid disorders in subfertile men consulting a tertiary referral center for reproductive medicine.

Thyroid autoimmunity and female infertility.

In infertile women, the prevalence of thyroid autoimmunity (TAI) is significantly higher compared to that in parous age-matched women. This is especially the case in women with endometriosis and the polycystic ovarian syndrome. TAI does not interfere with normal fetal implantation and comparable pregnancy rates have been observed after assisted reproductive technology (ART) in women with and without TAI. During the first trimester however, pregnant women with TAI carry a significantly increased risk for a miscarriage compared to women without TAI, even when euthyroidism was present before pregnancy. It has further been demonstrated that controlled ovarian hyperstimulation (COH) in preparation for ART has a significant impact on thyroid function, particularly in women with TAI. It is therefore advised to measure thyroid function and detect TAI in infertile women, before ART, and to follow-up these parameters after COH and during pregnancy when TAI was initially present. Women with thyroid dysfunction before or at early gestation stages should be treated with 1-thyroxine to avoid assisted pregnancy or further pregnancy complications. Whether thyroid hormones should be given prior to or during pregnancy in euthyroid women with TAI remains controversial and needs further investigation.

Variability among five different commercial IGF-1 immunoassays in conditions of childhood-onset GH deficiency and GH therapy.

IGF-1 measurement is used for screening of GH deficiency and monitoring of GH therapy in children. However, several commercial immunoassays are currently used and reference values provided by manufacturers are very different. The aim of this study was to compare commercial IGF-1 assays 1) in terms of absolute values and 2) in terms of clinical interpretation of results based on IGF-1 reference values in serum samples from children with GH therapy, with untreated GH deficiency and with obesity. Serum samples of 9 patients were sent frozen to 5 university hospitals using 5 different IGF-1 assays. The inter-laboratory coefficient of variation (CV) was calculated for the 9 samples. For clinical interpretation, results were expressed as SD scores based on reference values provided by manufacturers (and used in these laboratories). The mean inter-laboratory CV (range) for the 9 serum samples was 25.8% (16.7-35.9%). Major variability was noted in the SD-scores between IGF-1 assays for 3 tested serum samples from GH-treated patients with a difference between the lowest and highest SD score of 2.6 up to 3.2. In conclusion, there is a large variability among commercial IGF-1 immunoassays, not only in terms of absolute values, but also in terms of clinical interpretation in pediatric serum samples. There is a need for IGF-1 immunoassay harmonization and for the establishment of adequate reference values.