Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of > 17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy.

Per-operative hemodynamic instability in normotensive patients with incidentally discovered pheochromocytomas.

CONTEXT: The per-operative hemodynamic behavior of normotensive incidentally discovered pheochromocytomas is poorly documented. OBJECTIVE: To compare the per-operative hemodynamic instability and early postoperative outcome of normotensive pheochromocytomas, hypertensive pheochromocytomas, and benign non-pheochromocytoma adrenal incidentalomas (AIs). DESIGN: Retrospective cohort treated in a single center. PATIENTS AND METHODS: Fifty patients (10 normotensive pheochromocytomas, 24 hypertensive pheochromocytomas, and 16 AIs) were anesthetized and operated on by the same team, using laparoscopy in 78% of cases. Before surgery, 60% of normotensive and 95.8% of hypertensive pheochromocytomas received pretreatment with α-receptor or calcium channel blockers. All of the patients received the same intraoperative hemodynamic monitoring, including continuous direct intra-arterial pressure recording. RESULTS: All the features of hemodynamic instability, with the exception of the diastolic pressure nadir and fluid volume requirements, differed between hypertensive pheochromocytomas and AIs. Conversely, all features of hemodynamic instability were similar in hypertensive and normotensive pheochromocytomas. More specifically, by comparison with AIs, normotensive pheochromocytomas displayed higher maximal systolic pressure; more hypertensive, severe hypertensive, and hypotensive episodes; and a higher minimal heart rate, and also required more interventions to treat undesirable blood pressure elevations. Postoperative complications, all of which were mild, were more frequent in hypertensive pheochromocytomas than in normotensive pheochromocytomas (P < .03). CONCLUSIONS: Normotensive pheochromocytomas have roughly comparable per-operative hemodynamic instability to hypertensive pheochromocytomas and differ markedly from non-pheochromocytoma AIs. It is therefore crucial to identify normotensive pheochromocytomas among AIs when surgery is scheduled and to apply the standard of care for pheochromocytoma anesthesia.

Oral contraception but not menstrual cycle phase is associated with increased free cortisol levels and low hypothalamo-pituitary-adrenal axis reactivity.

BACKGROUND: In females, estrogen is a potential modulator of cortisol response to stressors. The aim of this study was to determine the influence of menstrual cycle phase, oral contraception (OC) use and exercise training on hypothalamo-pituitary-adrenal (HPA) axis activity and reactivity after physical stress. AIM: We investigated the effects of the menstrual cycle and OC use on exhaustive exerciseinduced changes in free salivary cortisol concentrations and free urinary cortisol/cortisone excretion in healthy young women. MATERIALS AND SUBJECTS: Twenty-eight women were allocated to an untrained group (no.=16) or a trained group (no.=12), depending on their physical training background. The untrained group was composed of nine OC users (UNTOC+) and seven eumenorrheic women (UNT-OC-) tested in the follicular and luteal phases, while the trained group was entirely composed of OC+ subjects (T-OC+). METHODS: Three laboratory sessions were conducted in a randomised order: a prolonged exercise test, a short-term exercise test, and a control session. For each session, urine and saliva specimens were collected at rest (09:00 h) and then, 30, 60 and 90 min later. RESULTS: Estradiol fluctuation during the menstrual cycle phase did not alter free cortisol baseline values and responses to exercise. OC use was associated with increased free resting salivary concentrations and urinary cortisol excretion with blunted salivary cortisol response to prolonged exercise stimulation. No training effect was noted. CONCLUSIONS: OC but not menstrual cycle phase is associated with increased free cortisol levels and low HPA axis reactivity.

Nocturnal activity of 11ß-hydroxy steroid dehydrogenase type 1 is increased in type 1 diabetic children.

AIM: The objective of this study was to investigate low-grade inflammation in children with type 1 diabetes (T1D) and its association with cortisol levels as well as its bioavailability through 11ß-hydroxy steroid dehydrogenase type 1 (11ß-HSD1) activity. METHODS: Children with T1D (n=45) and their non-diabetic siblings (n=28) participated in the study. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRPhs) were measured between 1400 and 1800h. Glucocorticoid metabolites were measured in the first morning urine on clinic day and 11ß-HSD1 activity was estimated by tetrahydrocortisol/tetrahydrocortisone (THF/THE) ratio. RESULTS: Diabetic patients presented with an increased THF/THE ratio compared with controls (median: 0.68 [range: 0.45-1.18] vs 0.45 [0.27-0.98], respectively; P<10(-3)). There was no difference between diabetic patients and controls for IL-6 (0.6ng/mL [0.6-6.8] vs 0.6 [0.6-2.2], respectively; P=0.43) and CRPhs (0.4mg/L [0-7.4] vs 0.3 [0-8.2]; P=0.26, respectively). When adjusted for age, gender and BMI, the THF/THE ratio was significantly associated with CRPhs (ß=0.32, P=0.02) in diabetic patients, but not in controls. CONCLUSION: Low-grade inflammation assessed by plasma CRPhs and IL-6 concentrations was not detectable in our cohort of T1D children. Nocturnal 11ß-HSD1 activity was increased and associated with plasma CRPhs concentration in diabetic patients. These results may be explained by either a direct or inflammation-mediated effect of the relative hepatic lack of insulin due to subcutaneous insulin therapy.

Use of an automated ACTH assay for the diagnosis of pituitary and adrenal-related diseases.

OBJECTIVE: To evaluate Liaison Diasorin's automated ACTH assay. DESIGN: We investigated the limit of quantification (LOQ) and simulated the usage of the analyzer using our ACTH results database. RESULTS: The LOQ was close to the cut-off determining Cushing's syndrome ACTH dependency. 25% concentrations of normal subjects were lower than the LOQ. Although biased, the results were concordant with those of an IRMA assay. CONCLUSION: This assay is not sensitive enough to diagnose ACTH-independent Cushing's syndrome.

Erythropoietin levels in endocrinopathies.

BACKGROUND: Erythropoietin (EPO) is an oxygenregulated hormone promoting the differentiation of erythroid progenitor cells. Apart fromhypoxia, few data is available about release by secretagogues including hormones. AIM: To investigate EPO serum concentration in subjects with endocrine diseases. MATERIAL AND METHODS: A retrospective study evaluating serumEPO concentrations in serumleftovers fromsubjects with various endocrine disorders. RESULTS: EPO is not noticeably influenced by thyroid hormone or cortisol concentrations and the relationship with hemoglobin concentration is preserved. In acromegalic patients, the latter is lost but EPO is neither statistically influenced by GH/IGF-I. This may reflect a dual action of GH and/or IGF-I on erythroid progenitors proliferation as well as on EPO synthesis. CONCLUSION: EPO is not noticeably modified by endocrine disorders although GH and or IGF-I may alter EPO relationship with blood hemoglobin concentration.

[Erythropoietin: indications and measurement]. / Erythropoïétine : Quand la prescrire ? Pourquoi et comment la doser ?

Erythropoietin (EPO) is the principal haematopoietic growth factor of the red blood cell line. Its major role is to stimulate the red blood cell production. EPO synthesis by peritubular cells in the kidney is regulated by oxygen concentration and must lead adaptation of the organism to face many different physiological situations. An imbalance can lead either to anaemia or polycythemia. Synthetic EPO, so-called recombinant, has definitively changed the treatment in the anaemia of chronic renal failure and regularly find new indications, legal (anaemia of cancer, anaemia of chronic inflammatory syndromes, myelodysplastic syndromes, neurology, cardiology...) or illegal (doping substance in sport). This article reviews the physiology, the role and the indications of EPO in clinical routine practice and define why and how EPO should be measured. We also focus on the analytical requirements for serum EPO concentration determination, especially in the differential diagnosis of polycythemias (secondary polycythemia/Polycythemia Vera).

Thyroid and gastric autoimmune diseases.

OBJECTIVES: Autoimmune thyroid disease (AITD) is frequently accompanied by other organ-specific diseases. We investigated the frequency of the association AITD-Biermer's disease (BD) in patients with AITD by investigating the prevalence of intrinsic factor antibodies (IF-Ab). DESIGN AND METHODS: Sera from 113 patients with AITD (hypo- or hyperthyroidism) were screened for the presence of type I IF-Ab with a competitive automated immunoassay based. Matched sera from 113 patients with dysthyroidism (not AITD) were tested. RESULTS: Four IF-Ab positive patients suffered from AITD. BD was known for two of them and strongly suspected in the two others. All patients with no AITD tested IF-Ab negative. B12 levels were often low whatever the etiology. CONCLUSION: The prevalence of IF-AbI is higher (3.5%) in patients with AITD. Prospective studies should investigate whether correcting thyroid dysfunction improves vitamin B12 levels, and establish whether routine screening for gastric autoimmunity is clinically useful or purely academic.

[What about bioavailable estradiol?]. / Dosage des stéroïdes sexuels sériques : quelle place pour l'estradiol biodisponible ?

Estradiol (E(2)) - similarly to testosterone - is a hormone mainly bound to SHBG and albumin in serum. Only the non SHBG-bound (free and albumin-bound hormone, i.e. bioavailable) hormone diffuses easily from circulation to tissues and is available for target cells. Bioavailable hormone measured or calculated seems to represent the best access to bioactive hormone concentration. Several studies reported that this bioavailable E(2) could be usefully measured for the understanding of chronic diseases in men or women, such as osteoporosis, cardiovascular disease and Alzheimer's disease. E(2) assays require a high sensitivity to assess low concentrations. It is currently difficult to know if bioavailable E(2) is really implicated or not in a given pathology but its interest is reported in many epidemiological studies.

Inter-strain differences in glucocorticoid and mineralocorticoid effects on macrophage and lymphocyte functions in mice.

We showed previously and we confirm here that macrophages from three mouse strains are differentially sensitive to the inhibition of expression of key inflammatory proteins (iNOS-II, IL-1 beta) by dexamethasone, a specific glucocorticoid receptor agonist (C57BL/6>DBA/2>BALB/c). Here we show that aldosterone (a specific mineralocorticoid agonist) has no effect on iNOS-II or IL-1 beta expression in macrophages from these mouse strains but decreases IL-1ra expression, with small inter-strain differences. This mechanism may be involved in the pro-inflammatory effect of this hormone. Concanavalin A-stimulated lymphocytes proliferation is also differentially sensitive to dexamethasone according to the strain, but insensitive to aldosterone.

[Is free plasmatic cortisol measurement useful in intensive care unit?]. / Mesure du cortisol libre plasmatique: un intérêt en réanimation?

Serum cortisol free fraction is responsible for its physiological function. Determination of serum total cortisol concentration does not allow accurate evaluation of hypothalamic pituitary adrenal axis when there is a quantitative variation in serum transcortin. Although free cortisol can be assayed by salivary or urinary cortisol measurements, these methods can not be easily applied in intensive care units. Free plasmatic cortisol measurement could provide a better reflect of circulating cortisol in patients with critical illness whom have a decreased concentration of binding proteins and whom adrenal status is an important prognostic factor. Free cortisol can be measured after separation from bound cortisol, calculated with equation based on equilibrium binding or evaluated by cortisol/CBG ratio. In various studies, free plasmatic cortisol allows in critical care patients a better appreciation of adrenal status than total cortisol and be more differential than total cortisol increment after stimulation with synacthen used to diagnose "relative adrenal insufficiency".

[About a case of congenital hypothyroidism]. / A propos d'un cas d'hypothyroïdie congénitale.

A boy presented at birth dyspnea, jaundice, meteorism and hypospadias; biochemical testing revealed hyponatremia. He benefited on day 4 of neonatal screening for hypothyroidism and congenital adrenal hyperplasia (CAH) and assays showed high concentrations of 17-OHP and TSH. Because of clinical features and hyponatremia, the diagnosis of CAH was plausible. A serum control (17-OHP and TSH) carried out on day 8 showed a normal concentration of 17-OHP and a persistently elevated concentration of TSH confirmed by a second assay a few days later. A 131I scan of neck revealed an ectopic lingual thyroid. The considerable progression of false positive screening tests for CAH is mainly due to the increasing number of premature babies. We show by a retrospective analysis (7 yrs), that children with hypothyroidism also present frequently higher concentrations of 17-OHP than normal children. However, whatever the aetiology (apart from CAH), the concentrations of 17-OHP rapidly normalise.

[Primary hyperaldosteronism]. / Dépistage biologique de l'hyperaldostéronisme primaire. Revue de la littérature.

Diagnosing primary aldosteronism, a hypertensive endocrine disease, is difficult because of an ill-defined frequency, various clinical forms and multiple diagnostic criteria. Current recommendations rest upon aldosterone and renin or renin activity determinations, the main point being to investigate aldosterone secretion with regards to of its main stimulus, renin. Proponents of the renin assay argue that it is easy and reliable. Proponents of the renin activity assay favour this method because of multiple epidemiological studies. Whatever the method used, each laboratory has to establish its critical thresholds in relation to the kits used. Extensive comparative studies would be useful to appreciate their relative benefits.

[Ac-SDKP, a marker of the angiotensin-converting enzyme activity?]. / L'Ac-SDKP: une clé pour comprendre certains effets des inhibiteurs de l'enzyme de conversion?

The tetra-peptide Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) generated by the cleavage of thymosine beta4 inhibits the proliferation of hematopoietic stem cells and the proliferation and secretion of fibroblasts in the myocardium and the glomeruli. The clinical administration of Ac-SDKP has been proposed and partially investigated. The peptide could protect hematopoietic stem cells during anti-neoplastic treatments leaving cancerous cells unprotected. As it opposes the effects of TGFbeta it could prevent fibrosis after myocardial infarcts and glomeruli fibrosis during the natural course of diabetic nephropathy. However, until now the expected benefits of such a treatment are based on an indirect consideration. Indeed, the degradation of Ac-SDKP is due to the action of the angiotensin-converting enzyme. Interestingly, the blocking of this enzyme both improves the above-mentioned fibrosis and increases the plasma levels of Ac-SDKP. Should the therapeutic effects prove solid, and therapeutic levels be established assaying Ac-SDKP could be an interesting marker of therapeutic efficiency.

[Thyroglobulin mRNA detection in the follow-up of thyroid carcinomas]. / Détection des ARNm circulants de la thyroglobuline et surveillance des cancers thyroïdiens: revue de la littérature.

The follow-up of differentiated carcinomas is based on the detection of thyroglobulin (Tg) in the serum. Tg assays are immunoassays that may be hampered by autoantibodies directed against Tg. To avoid this problem some authors advocated the use of mRNA extraction and RT-PCR amplification. Quantitative methods have been developed to achieve a good analytical sensitivity. These techniques may then be alternative to the Tg assay when anti-Tg antibodies are present in the serum should it be proven they display pronostic values reliable enough for clinical diagnosis use.

[I131 in blood samples: management in the laboratory]. / Gestion au laboratoire d'échantillons de sang de patients traités par iode radioactif.

OBJECTIVES: Patients treated by (131)I may require blood sampling in the days following its administration. We investigated the safety of such samples in terms of radioactivity and the possible disturbance of the analyses by these "131I-spiked" samples. METHOD: 1) The radioactivity of blood samples from 131I-treated patients was measured (dose rate, surface activity, total activity) ; 2) The risk for the personnel was subsequently evaluated and ; 3) The interference of this 131I-generated radioactivity on the results of routine automated and IRMA assays was investigated. RESULTS: 1) All RA measures but two were found below the European limits ; 2) Irradiation of personnel was negligible ; 3) The faint radioactivity did not disturb any analyses. CONCLUSION: These data demonstrate the safety that results from the negligible radioactivity in these blood samples.

Fat distribution in obese women is associated with subtle alterations of the hypothalamic-pituitary-adrenal axis activity and sensitivity to glucocorticoids.

OBJECTIVES: Obesity with abdominal body fat distribution (A-BFD) and hypothalamic-pituitary-adrenal (HPA) axis activity are somehow linked, but the exact interactions still need clarification. Obese subjects display normal circulating plasma cortisol concentrations with normal circadian rhythms. However, when the HPA axis is pharmacologically challenged, body fat distribution matters and then A-BFD obese women differ from those with subcutaneous body fat distribution (P-BFD). We hypothesized that lower dose provocative and suppressive tests than those used to diagnose hypercortisolism of tumour origin or adrenal insufficiency would shed some light on the characteristics of the HPA axis activity in relation with body fat distribution. PATIENTS AND METHODS: Fifty premenopausal obese women were grouped according to their body fat mass distribution. Their plasma cortisol responses to (i) two low doses of dexamethasone (0.25 and 0.5 mg) with (ii) low dose of the ACTH analogue tetracosactrin (1 microg) were assessed. Salivary cortisol was also determined during the ACTH test. RESULTS: A-BFD differed from P-BFD women in terms of HPA axis responsiveness. They had comparatively: (i) increased nocturnal cortisol excretion (9.38 +/- 2.2 vs. 6.82 +/- 0.91 nmol/micromol creatinine, A-BFD vs. P-BFD, respectively, P = 0.03); (ii) increased salivary cortisol response to ACTH stimulation (1 microg) [salivary cortisol peak: 33.4 (14.1-129) vs. 28.5 (13.2-42.8) nmol/l; salivary AUC: 825 (235-44738) vs. 537 (69-1420) nmol/min/l; A-BFD vs. P-BFD, P = 0.04 for both]; and (iii) increased pituitary sensitivity to dexamethasone testing [postdexamethasone (0.25 mg) plasma cortisol levels: 163 (26-472) vs. 318 (26-652) nmol/l and postdexamethasone (0.5 mg) plasma cortisol levels: 26 (26-79) vs. 33 (26-402) nmol/l; A-BFD vs. P-BFD, P = 0.01 for both). CONCLUSIONS: These data demonstrate differences in the HPA axis activity and sensitivity to glucocorticoids between obese women differing in their body fat distribution, with both enhanced negative and positive feedback in those with abdominal obesity. Several mechanisms may explain these differences: central vs. peripheral hypotheses. Thus, abdominal obesity does not appear to be linked solely to one pathophysiological hypothesis.