Digestive symptoms in daily life of chronic adrenal insufficiency patients are similar to irritable bowel syndrome symptoms.

Gastrointestinal symptoms are frequent in acute adrenal insufficiency. Although digestive symptoms can significantly reduce quality of life, they are rarely described in patients with treated chronic adrenal insufficiency (CAI). We aimed to characterize digestive symptoms in CAI patients. We used the section pertaining functional bowel disorders of the Rome IV questionnaire. A questionnaire was published on the website of the non-profit patient association "Adrenals" (NPPA of CAI patients) for five months. Information on demographics, characteristics of adrenal insufficiency, digestive symptoms and quality of life was collected. The relatives of CAI patients served as a control group. We analyzed responses of 33 control subjects and 119 patients (68 primary adrenal insufficiency (PAI), 30 secondary adrenal insufficiency (SAI) and 21 congenital adrenal hyperplasia (CAH)). Abdominal pain at least once a week over the past 3 months was reported by 40%, 47% and 33% of patients with PAI, SAI and CAH respectively versus 15% for the controls (p = 0.01). Symptoms were consistent with the Rome IV criteria for irritable bowel syndrome in 27%, 33% and 33% of patients respectively versus 6% for the controls (p < 0.0001). Quality of life was described as poor or very poor in 35%, 57% and 24% of patients respectively versus 5% for the controls (p < 0.0001). In conclusion, digestive symptoms are frequent and incapacitating in CAI patients and similar to symptoms of irritable bowel syndrome in 30% of CAI patients. Assessment and management of digestive symptoms should be considered a priority for physicians treating patients with CAI.

Verneuil's disease, innate immunity and vitamin D: a pilot study.

BACKGROUND: Verneuil's disease is a chronic inflammatory skin disease of the follicles in apocrine glands rich area of the skin (axillary, inguinal, anogenital) and is associated with a deficient skin innate immunity. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. Recently, vitamin D has been shown to stimulate skin innate immunity. OBJECTIVE: The primary objective of the study was to assess whether Verneuil's disease was associated with vitamin D deficiency. The secondary objective was to determine whether vitamin D supplementation could improve inflammatory lesions. METHODS: First, 25(OH) vitamin D3 serum levels in patients with Verneuil's disease followed at Nantes University Hospital were compared to those of healthy donors from the French Blood Bank. Then, a pilot study was conducted in 14 patients supplemented with vitamin D according to their vitamin D level at baseline at months 3 and 6. The endpoints at 6 months were decreased by at least 20% in the number of nodules and in the frequency of flare-ups. RESULTS: Twenty-two patients (100%) had vitamin D deficiency (level <30 ng/mL) of whom 36% were severely deficient (level <10 ng/mL), having correlation with the disease severity (P = 0.03268) vs. 20 controls with vitamin D deficiency (91%) of whom 14% were severely deficient. In 14 patients, the supplementation significantly decreased the number of nodules at 6 months (P = 0.01133), and the endpoints were achieved in 79% of these patients. A correlation between the therapeutic success and the importance of the increase in vitamin D level after supplementation was observed (P = 0.01099). CONCLUSION: Our study shows that Verneuil's disease is associated with a major vitamin D deficiency, correlated with the disease severity. It suggests that vitamin D could significantly improve the inflammatory nodules, probably by stimulating the skin innate immunity. A larger randomized study is needed to confirm these findings.

Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen.

OBJECTIVES: Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. PATIENTS AND METHODS: We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, ß2-microglobulin and α1-microglobulin were measured during a routine clinical visit. RESULTS: Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. CONCLUSIONS: Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited.

[An exceptional component C3 deficiency revealed by serum protein electrophoresis]. / Un exceptionnel déficit héréditaire en fraction C3 du complément dépisté par électrophorèse des protéines sériques.

We report the case of a 5-years old child referred to the pediatric clinic due to a prolonged history of recurrent otitis. Initial immunologic investigation was normal but a severe C3 complement deficiency was detected by the absence of beta 2-globulin protein fraction using serum protein capillary electrophoresis. C3 was not detected in serum and total complement haemolytic activity was decreased. His mother and father had half of the C3 normal plasma level and a heterozygous mutation of the C3 gene. The diagnosis of hereditary deficiency of the third complement component (C3) with compound heterozygous mutation of the gene was made. This defect in complement protein C3, described to date in only 20 families in the world, is associated with repeated infections. The child is treated with oracillin with relatively good control of symptoms.

[Contribution of the laboratory in hypoglycemia diagnosis induced by insulin administration in a 2-year-old girl]. / Apport du laboratoire dans le diagnostic d'une hypoglycémie liée à des injections d'insuline chez un enfant de 2 ans.

We report the case of a 2 year-old child presented to the emergency department following a seizure. The child was hypotonic and examination was unremarkable but laboratory tests confirmed a severe hypoglycaemia. The insulin level, inappropriately high for the glycemia and the peptide C undetectable suggested exogenous hyperinsulinism. We conclude that the hypoglycaemia was likely the result of Munchhausen syndrome by proxy. The specificity of two immunoassays used (Elecsys Roche and IRMA CisBio) for the synthetic analogues of insulin explains the discrepancy between the insulin levels obtained but was crucially useful to the approach of the cause of the hypoglycaemia.

Anti-mullerian hormone: clinical relevance in assisted reproductive therapy.

Anti-Müllerian Hormone (AMH) is a member of the transforming Growth Factor-B (TGF-B) family synthesized exclusively by the gonads of both sexes. Over the last four years, numerous studies have examined the clinical usefulness of serum AMH levels as a predictor of ovarian response and pregnancy in assisted reproductive technology cycles. Assessment of ovarian reserve in women undergoing assisted reproduction is useful in optimising the treatment protocol. Availability of a reliable measure of ovarian reserve is essential. Currently, serum AMH level seems to be more strongly related to the ovarian reserve and to be a more discriminatory marker of assisted reproductive technology outcome than follicle-stimulating hormone, inhibin B or estradiol, which are more commonly used markers. Our study involving 69 women undergoing a cycle of in vitro fertilisation (IVF) or intracytoplamic sperm injection (ICSI) treatment, confirmed these results. We have shown in this study that AMH is significantly correlated with the number of eggs collected and is of great interest as a negative predictive value for the success of assisted reproductive technology (ART). Further studies are needed to determine AMH cut-off values.

[Central hypothyroidism associated with bexarotene therapy]. / Une étiologie d'hypothyroïdie à ne pas méconnaître: l'hypothyroïdie centrale associée au traitement par bexarotène Targretin.

We report the case of a patient with cutaneous T-cell lymphoma treated by bexaroten Targretin, a synthetic retinoid analog with specific affinity for retinoid X receptor. The treatment induced mixed hyperlipidemia and severe central hypothyroidism characterized by reduced TSH and thyroxine serum levels. Only the pituitary thyreotrope function was affected. Targretin therapy can be maintained. Adverse drug events may be managed by fenofibrate Lipanthyl for dyslipidemia and high dose L-thyroxin Lévothyrox requiring serum free thyroxin level measurement for central hypothyroidism.

Phosphohistone H3 labelling for histoprognostic grading of breast adenocarcinomas and computer-assisted determination of mitotic index.

BACKGROUND: Microscopic evaluation of mitotic figures is a routine procedure in the assessment of the histoprognostic grade of tumours. Nevertheless, their count may be fraught with difficulties. As histone H3 phosphorylation at serine 10 is closely linked to chromosomal condensation, a new monoclonal antibody directed to phosphorylated histone H3 (PPH3) was recently proposed to detect mitotic cells. AIM: To test the reliability of this antibody in detecting and counting mitotic figures in sections of breast adenocarcinomas, because of the importance of mitotic count in histoprognostic grading. METHODS: The pattern of PPH3 staining in formalin-fixed paraffin wax-embedded tissues, including normal tissues and a series of 39 breast adenocarcinomas, was examined. A new computer-assisted method was also developed for determining the mitotic index. RESULTS AND CONCLUSIONS: In all tissues tested, PPH3-labelled mitotic figures were easily detected, allowing a rapid identification of the area of highest mitotic activity. In breast carcinomas, a strong correlation was observed between PPH3-stained and haematoxylin and eosin-stained mitotic counts (r = 0.86, p<0.0001). Counting of prophase nuclei that coexpress cyclin B1, a marker of the G2/M phase, was possible by PPH3 staining; its accuracy led us to reconsider the tumour grade in three cases. Finally, an automatic computer-assisted method was designed for assessing mitotic index with confocal microscopy and image-analysis software.

Influence of atorvastatin on apolipoprotein E and AI kinetics in patients with type 2 diabetes.

Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([(2)H3]leucine-primed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 +/- 19.1 versus 32 +/- 11.6 mg/l, p < 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 +/- 6.71 versus 13.37 +/- 6.05 mg/l, p < 0.05) and production rate (0.202 +/- 0.085 versus 0.119 +/- 0.047 mg/kg/day, p < 0.05), whereas an increase in VLDL-apoE concentration (6.44 +/- 2.16 before versus 9.23 +/- 4.02 mg/l after, p < 0.05) and production rate (0.827 +/- 0.367 versus 1.524 +/- 0.664 mg/kg/day, p < 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.

[Dysalbuminemia]. / Les dysalbuminémies.

Albumin is the major circulating protein. It plays a fundamental role maintaining intra-vascular oncotic pressure and carrying many endogenous and exogenous substances. Variations of plasma albumin levels can be physiologic or pathologic and both qualitative and quantitative (more frequent) disorders are regrouped under the name "dysalbuminemia". Although hypoalbuminemia are frequent, analbuminemia exists but is a rare disease. Qualitative disorders, mainly bisalbuminemia, are benign. Detected fortuitously on sera protein electrophoresis, bisalbuminemia could be genetically transmitted, it will then be permanent, or acquired and then be transient. This article proposes to review main kind of dysalbuminemia usually encountered in clinical biology laboratories.

[Clinico-biological evaluation of malnutrition]. / Evaluation clinico-biologique de la dénutrition.

Malnutrition is frequently observed at hospital, concerning 30 to 50% of hospitalised patients. Increased length of stay and cost of care has made of this problem a major economic stake. Indeed, malnutrition diagnosis and prevention has become, since 2001, one of major french government's priority. Malnutrition results from unbalanced nutritional requirement and in-take. It associates both weight, proteic and functional loss. Its diagnosis and evaluation of its gravity are first clinical and need body mass index determination. For biological diagnosis, nutritional markers have to be very sensitive to nutritional state. Nutritional profile can be made, associating two nutritional markers (albumin and transthyretin) and one inflammation protein (alpha 1-acid-glycoprotein). Various clinical, biological or clinico-biological indexes can also be calculated. Altogether, both indexes and nutrition profile are excellent tools for (1) diagnosis and classification of malnutrition state, moderate or severe, (2) prognostic and (3) evaluation of nutritional supplementation efficiency.

Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes.

BACKGROUNDS AND AIMS: Insulin resistance related to obesity and diabetes is characterized by an increase in plasma TG-rich lipoprotein concentrations. Apolipoprotein (apo) E plays a crucial role in the metabolism of these lipoproteins and particularly in the hepatic clearance of their remnants. The aim of this study was to explore apoE kinetics of obese subjects and to determine what parameters could influence its metabolism. METHODS: Using stable-isotope labelling technique ([(2)H(3)]-leucine-primed constant infusion) and monocompartmental model (SAAM II computer software), we have studied the plasma kinetics of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoE in 12 obese subjects (body mass index (BMI) 27.4-36.6 kg/m(2)): Seven were type 2 diabetics (age 47-65 y; HbA1c 7.1-10.2%) and five were non-diabetics (age 40-51 y, HbA1c: 4.9-5.3%). Six of the diabetic subjects were insulin resistant as assessed by insulin sensitivity index (HOMA 2.6-10.0), while non-diabetic subjects were all insulin sensitive (HOMA 1.2-2.1). RESULTS: Plasma VLDL and HDL apoE concentrations were significantly higher in diabetic than in non-diabetic subjects (5.74+/-1.60 vs 1.46+/-1.74 mg/l, P<0.01 and 17.81+/-6.67 vs 9.97+/-3.32 mg/l, P<0.05). These increased levels were associated with significantly higher absolute production rate (APR) of VLDL and HDL apoE (0.714+/-0.343 vs 0.130+/-0.200 mg/kg/day, P<0.01, and 0.197+/-0.087 vs 0.080+/-0.060 mg/kg/day, P<0.05, respectively) while no significant difference was found for fractional catabolic rate (FCR) of VLDL and HDL apoE (3.44+/-1.64 vs 1.97+/-0.84/day and 0.30+/-0.12 vs 0.19+/-0.09/day, respectively). In the whole population, BMI was not correlated with any of apoE kinetic data. HOMA was positively correlated with FCR of VLDL apoE (r=0.64, P<0.05) and tended to be correlated with APR of VLDL apoE (r=0.58, P=0.06). HbA1c was positively correlated with APR and FCR of both VLDL apoE (r=0.91 and 0.78, P<0.01, respectively) and HDL apoE (r=0.66 and 0.69, P<0.05, respectively). CONCLUSION: Obese diabetics are characterized by elevated VLDL and HDL apoE levels associated with enhancement of VLDL and HDL apoE production rates. Whereas obesity did not influence apoE kinetic parameters in itself, insulin resistance may lead to an increase in VLDL apoE production and fractional catabolic rates. Diabetes and the glycemic control may also specifically influence the kinetics of both VLDL and HDL apoE. All together, these disorders should explain at least part of the increase in VLDL and HDL apoE observed in diabetes.

Influence of remnant accumulation markers on plasma concentrations of two lipoprotein(a) subspecies (containing or free of apoE).

Lipoprotein(a) [Lp(a)], an atherosclerosis marker, has 2 subspecies differing in structure and composition that can easily be distinguished by the presence or absence of apolipoprotein E (apoE). The subspecies containing apo E [Lp(a):B:E] is found mainly in the very-low-density lipoprotein (VLDL) size range, while that free of apoE [Lp(a):B] is found mainly in the LDL size range. As little is known about the physiologic function of these subspecies, this study investigated Lp(a):B and Lp(a):B:E concentrations in a population of normotriglyceridemic and moderately hypertriglyceridemic subjects in fasting state and attempted to determine the parameters influencing their plasma concentrations. The subjects studied (n = 98) had a mean total Lp(a) concentration of 108 mg/dL (28 to 252, minimum to maximum), a mean Lp(a):B concentration of 92.6 mg/dL (5 to 254), and a mean Lp(a):B:E concentration of 15.6 mg/dL (0 to 137). These results indicate that Lp(a):B:E, even in normolipidemic subjects, constitutes a detectable part of total Lp(a), ie, a mean percentage of 16.2% (0% to 96%). Multiple stepwise regression analyses showed that triacylglycerol has no independent effect on the concentration of Lp(a) subspecies, and that remnant accumulation markers, such as the E/LpB:E molar ratio (number of apoE per particle containing both apoB and apoE) and apoE-LpB (mass of apoE bound to particles containing both apoB and apoE), have a strong independent effect on this concentration. A strong positive influence of E/LpB:E on Lp(a):B:E subspecies was noted, as well as a negative influence of apo E-LpB on Lp(a):B subspecies. Taken together, these results suggest that the apoE bound to LpB:E particles plays a dominant role in the concentration of Lp(a) subspecies and that a redistribution of Lp(a) subspecies occurs under the influence of the apoE content of triacylglycerol-rich lipoprotein particles.

Negative and independent influence of apolipoprotein E on C-reactive protein (CRP) concentration in obese adults. Potential anti-inflammatory role of apoE in vivo.

BACKGROUND: Obesity is frequently associated with an increase in the early inflammation marker C-reactive protein (CRP), insulin resistance and changes in lipoprotein metabolism. Increased CRP is known as an independent cardiovascular risk factor. Since the apolipoproteins (apo) E and CIII components of HDL are associated with reduced cardiovascular risk and since apoE has in vitro anti-inflammatory effect, we have investigated the relationships between apoE, apoCIII (in apoB and non apoB containing lipoproteins) and CRP in obese adults. METHODS: The following parameters from 34 healthy obese fasting women (age 22-64 y, body mass index (BMI) 28-68 kg/m2) were measured: (1) ApoE and apoCIII, in total plasma, in apoB- (E LpB, CIII LpB) and non-apoB-containing lipoproteins (E LpnonB, CIII LpnonB); (2) CRP and cytokine secreted by adipose tissue (TNF-alpha and its soluble receptor TNFR2); (3) triglyceride, HDL-cholesterol, systolic blood pressure, diastolic blood pressure, waist and hip circumferences, insulin, glucose. HOMA, a marker of insulin sensitivity, and the ratio E/CIII in LpB and LpnonB were calculated. RESULTS: CRP was positively correlated with BMI (P<0.05), waist circumference (WC, P<0.05), triglyceride (P<0.05) and negatively correlated with apoE (P<0.01) and E LpnonB (P<0.05). Two multiple regression models including parameters related to CRP with a P<0.25 were run stepwise to assess their independent contribution to CRP concentration. In the first model (including BMI, WC, HOMA, insulin, triglyceride, apoE, E LpnonB), apoE was the best predictor of CRP (P=0.01) together with triglyceride (P=0.02) and BMI (P=0.08). The second model took into account E/CIII LpnonB ratio with the parameters included in the first model. In this second model, E/CIII LpnonB was the best predictor of CRP (P=0.007), explaining 39% of CRP variance. CONCLUSION: ApoE is strongly correlated with CRP and could have an anti-inflammatory effect in vivo in obese subjects. This correlation could be limited to LpnonB lipoproteins, depending on their apoE and CIII relative content.