Aggregation of autoimmunity in extended families of people with autoimmune Addison disease.

BACKGROUND: Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison disease (AD)). Affected people present a significant co-occurrence of autoimmune conditions; hence, clustering of autoimmunity is also predicted among their relatives. AIMS: To evaluate the burden of autoimmunity in families of people with AD. METHODS: A total of 116 individuals with AD was surveyed regarding the occurrence of 23 autoimmune diseases among their relatives. RESULTS: A total of 74.1% of persons with AD reported at least one relative with an autoimmune disorder - 257 cases were diagnosed in 221 relatives. Hashimoto thyroiditis was found in 100 individuals, followed by Graves disease and vitiligo, in 25 and 24 relatives respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, and premature menopause in 8 women. AD was found in seven relatives, alopecia in six and celiac disease in five. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (P = 0.031). A total of 66.4% of people with AD had a first-degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (P < 0.001), mothers (P = 0.002) and grandmothers (P = 0.002). CONCLUSIONS: Considerable prevalence of autoimmune conditions in relatives of people with AD confirms substantial risk of autoimmunity, especially in females and relatives of patients affected by multiplex autoimmunity. Our data corroborate the recommendation of active screening for autoimmune disorders, particularly thyroid disease, among AD family members.

Serum Visfatin does not seem to be a Useful Marker to Guide Glucocorticoid Substitution in Adrenal Insufficiency.

Primary adrenal insufficiency (Addison's disease, AD) requires lifelong steroid substitution. Excess exogenous glucocorticoids promote abdominal obesity, insulin-glucose imbalance, and hypertension. Reliable markers of the adequate glucocorticoid replacement are lacking. Visfatin is a pro-inflammatory adipokine, with enzymatic activity of nicotinamide phosphoribosyltransferase. It enhances leukocyte function and synthesis of tumour necrosis factor α (TNFα) and interleukin-6 (IL-6). Serum visfatin is elevated in autoimmunity, but also in obesity, insulin resistance, and metabolic syndrome. This study was aimed to investigate whether serum visfatin could guide the glucocorticoid substitution in AD. Biochemical analyses were performed in 96 patients with AD (mean age 43.3±14.9 years) and 91 controls (43.5±12.5 years). Visfatin level was significantly elevated in patients with AD compared to controls (p<0.0001). Higher circulating IL-6 was also detected among subjects with AD (p=0.006). In AD, visfatin level was positively correlated with IL-6 (p=0.014), TNFα (p=0.001), body mass (p=0.015), fasting insulin (p=0.001) and HOMA-IR (p=0.001). No relationship was noticed with daily hydrocortisone (p=0.096) and urinary free cortisol excretion (p=0.499). Only the correlations with IL-6 and fasting insulin survived multiple regression analysis (p=0.049 and p=0.005, respectively). Additionally, positive correlation between visfatin and autoantibodies to 21-hydroxylase was noted (p=0.005). In the control group serum visfatin was correlated with IL-6 (p=0.009) and TNFα (p=0.0002). The current study reveals elevated serum visfatin in autoimmune AD. Visfatin does not seem a useful marker of the glucocorticoid replacement, although it correlates with fasting insulin and pro-inflammatory molecules. Further functional analyses are warranted to elucidate the role of visfatin in autoimmunity.

A genome-wide association study on medulloblastoma.

INTRODUCTION: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report.

Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

INTRODUCTION: Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic ß cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon γ production, and development of Th17 cells. Polymorphisms of STAT4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent results. This analysis was designed to investigate the association of STAT4 rs7574865 with T1D in Polish children and to assess STAT4 expression in newly diagnosed subjects. MATERIAL AND METHODS: Rs7574865 was genotyped in 656 T1D children and 782 healthy individuals. STAT4 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 29 children with T1D and 27 age-matched controls. ß-cell and thyroid-specific serum autoantibodies were assessed with radioimmunoassays. RESULTS: The distribution of rs7574865 genotypes and alleles demonstrated significant difference (p = 0.002, p < 0.001, respectively) between patients vs. controls. Carriers of the minor T allele presented earlier T1D onset (p = 0.017). No differences were found in γ-cell autoantibody in genotype-stratified patients (p > 0.050), while anti-thyroid antibodies were more frequent in carriers of the minor allele(p = 0.039 for anti-thyroperoxidase, p = 0.007 for anti-thyroglobulin antibodies, respectively). STAT4 was overexpressed in PBMCs from T1D patients (p = 0.008), especially subjects with two/three circulating ß-cell antibodies (p < 0.001). CONCLUSIONS: The study confirms an association of STAT4 rs7574865 with T1D in Polish patients, and provides an evidence for its relationship with an earlier disease onset and concomitant thyroid autoimmunity. STAT4 expression appears elevated in T1D, especially with more severe reaction against ß-cell antigens.

Determination of 21-hydroxylase autoantibodies: inter-laboratory concordance in the Euradrenal International Serum Exchange Program.

BACKGROUND: 21-Hydroxylase autoantibodies (21OHAb) are markers of an adrenal autoimmune process that identifies individuals with autoimmune Addison's disease (AAD). Quality and inter-laboratory agreement of various 21OHAb tests are incompletely known. The objective of the study was to determine inter-laboratory concordance for 21OHAb determinations. METHODS: Sixty-nine sera from 51 patients with AAD and 51 sera from 51 healthy subjects were blindly coded by a randomization center and distributed to 14 laboratories that determined 21OHAb, either by an "in-house" assay (n=9) using in vitro-translated (35)S-21OH or luciferase-labeled 21OH or a commercial kit with (125)I-21OH (n=5). Main outcome measures were diagnostic accuracy of each participating laboratory and inter-laboratory agreement of 21OHAb assays. RESULTS: Intra-assay coefficient of variation ranged from 2.6% to 5.3% for laboratories using the commercial kit and from 5.1% to 23% for laboratories using "in-house" assays. Diagnostic accuracy, expressed as area under ROC curve (AUC), varied from 0.625 to 0.947 with the commercial kit and from 0.562 to 0.978 with "in-house" methods. Cohen's κ of inter-rater agreement was 0.603 among all 14 laboratories, 0.691 among "in-house" laboratories, and 0.502 among commercial kit users. Optimized cutoff levels, calculated on the basis of AUCs, increased the diagnostic accuracy of every laboratory (AUC >0.9 for 11/14 laboratories) and increased the Cohen's κ of inter-rater agreement. Discrepancies in quantitation of 21OHAb levels among different laboratories increased with increasing autoantibody levels. CONCLUSIONS: The quality of 21OHAb analytical procedures is mainly influenced by selection of cutoff value and correct handling of assay materials. A standardization program is needed to identify common standard sera and common measuring units.

The role of antithyroglobulin, antiperoxidase and anti-TSH receptor autoantibodies in amiodarone-induced thyrotoxicosis and amiodarone-induced hypothyroidism (A two-center study).

OBJECTIVE: It has been reported that patients experiencing side effects of amiodarone (AM) therapy, such as amiodarone-induced thyrotoxocosis (AIT) or amiodarone-induced hypothyroidism (AIH), have changes in serum concentrations of anti-TSH receptor (TSHR), antithyroglobulin (Tg), and antiperoxidase (TPO) autoantibodies (Abs). The purpose of our study was to identify and analyze the changes in levels of listed antibodies in patients with several thyroid disorders. METHODS: 280 patients from two centers in Poland were included. Titers of TSHR-Abs, TPO-Abs and Tg-Abs were analyzed retrospectively in the following groups of patients: A - euthyroid patients with a history of hyperthyroidism prior to re-administration of AM; B - patients with AIT who discontinued the AM therapy; C - patients with AIT chronically treated with AM; D - hypothyroid patients. RESULTS: Serum Tg-Abs were not elevated in any of the studied groups. However, there were significant differences between A and B and also D and other groups (p<0.05). TPO-Abs titers were not elevated in most cases, there were no significant differences between groups. The serum titers of TSHR-Abs were not elevated in any group. We found statistically significant differences between B and D, C and other groups (p<0.05). CONCLUSIONS: Regardless of the statistically significant differences observed for Tg-Abs and TSHR-Abs levels, this observation have a limited clinical applicability. In almost all cases we observed normal to slightly increased titers of TPO-Abs, Tg-Abs, TSHR-Abs. Discontinuation or continuation of AM therapy had no influence on autoantibody titers. Furthermore, we found it impossible to differentiate between the type I and II of AIT based on autoantibody titers.

Pneumocystis pneumonia in children - the relevance of chemoprophylaxis in different groups of immunocompromised and immunocompetent paediatric patients.

INTRODUCTION: Pneumocystis jirovecii is an opportunistic pathogen causing pneumocystis pneumonia (PCP), a life-threatening infection, in immunocompromised patients. In this study, retrospective analysis of the presence of P. jirovecii DNA in different samples collected from children with suspected PCP was carried out. MATERIAL AND METHODS: Three hundred and six specimens [152 bronchoalveolar lavage (BAL) specimens, 80 blood specimens, 18 bronchial secretions (BS), 34 induced sputum samples, 10 endotracheal aspirates (ETA), and 12 other type samples] obtained from patients with suspected PCP were examined by real-time PCR. RESULTS: Forty (13.1%) patients were positive for P. jirovecii: 4 (7.7%) patients with malignancies, 3 (6.8%) transplant recipients, 15 (23.1%) other immunocompromised patients, and 18 (12.4%) immunocompetent patients. Pneumocystis jirovecii DNA was detected in 20.4% of BAL specimens, 11.1% of BS samples, 10% of ETA sample, 8.8% of induced sputum samples, and in 3.7% of blood samples. Comparing the frequency of the presence of P. jirovecii DNA between the group of children treated with PCP chemoprophylaxis (malignancy patients and transplant recipients) and a group of children not receiving this prophylaxis (other immunocompromised and immunocompetent children), we found that the occurrence of PCP was twice as high in the latter group of children (7.3% and 15.7%, respectively). CONCLUSIONS: Respiratory samples, such as BS, BAL, or ETA specimens, are the material of choice for the diagnosis of PCP. Due to high incidence of PCP in certain groups of immunocompetent and immunocompromised patients, besides cancer patients and transplant recipients, consideration of PCP prophylaxis is required in these groups as well.

Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

PURPOSE: Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. METHODS: Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). RESULTS: Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. CONCLUSION: Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

Polymorphisms in the interferon-induced helicase (IFIH1) locus and susceptibility to Addison's disease.

OBJECTIVE: The interferon-induced helicase C domain-containing protein 1 (IFIH1) gene encodes a sensor for double-stranded RNA that initiates antiviral activity against enteroviruses. Previous investigations have indicated a role for IFIH1 in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes. We hypothesized that polymorphisms in the IFIH1 locus may play a role in the pathogenesis of autoimmune Addison's disease (AAD). DESIGN: We analysed the association of rs3747517, rs1990760, rs2111485 and rs13422767 single-nucleotide polymorphisms (SNPs) in the IFIH1 gene and intergenic region with AAD in a Polish cohort. The study comprised 120 patients with AAD and 689 healthy control individuals. Genotyping was performed using TaqMan genotyping assays. RESULTS: The major AA genotype of the coding SNP rs1990760 appeared significantly more frequently in AAD compared with healthy individuals (AG vs AA OR 0·62, 95%CI 0·40-0·95, P = 0·03). We also observed a significant difference in the distribution of the rs13422767 SNP alleles. The major G allele was more frequent in the AAD group (A vs G OR 0·65, 95%CI 0·43-0·98, P = 0·04). Both statistically significant differences, for rs1990760 and rs13422767 SNPs, did not survive the Bonferroni correction (P = 0·11 and P = 0·15, for AA genotype and G allele, respectively). Subsequently, a meta-analysis of 519 patients with AAD and 1362 controls from three different European populations was performed. Under a fixed-effect model, a pooled OR for A allele and AA genotype of rs1990760 did not display any significant increase among AAD (OR = 1·05, P = 0·56 and OR = 1·08, P = 0·50, respectively). CONCLUSION: The IFIH1 locus polymorphisms are unlikely to be associated with Addison's disease.

Env gene expression of human endogenous retrovirus-k and human endogenous retrovirus-w in childhood acute leukemia cells.

INTRODUCTION: The etiopathogenesis of childhood leukemia is not fully understood. It is suggested that endogenous viral sequences may play a role in leukemogenesis. Human endogenous retroviruses (HERVs) constitute about 8% of the human genome. Most HERVs are dysfunctional because of numerous mutations and deletions. Some HERVs, however, contain sequences capable of transcription. In patients with leukemia, the presence of antibodies against HERV-K has been identified, which could suggest increased expression of HERV-K in leukemic cells. To elucidate the role of endogenous retroviruses in leukemogenesis, studies were undertaken to assess env gene expression of HERV-K and HERV-W in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). RESULTS: This study was performed in 170 children with ALL, 38 subjects with AML, and 30 healthy subjects. Expression of the env gene of HERV-K and HERV-W and the control gene ACTB was studied by real-time PCR using specific oligonucleotide primers and SYBR Green marker. Env gene expression was assessed on the basis of the absolute threshold-Ct, as well as normalized against ACTB expression and double normalized expression relative to ACTB and reference cells - normal peripheral blood lymphocytes (PBL). Env gene expression of HERV-K normalized against ACTB, as well as double normalized expression relative to ACTB and normal PBL, was significantly higher only in AML. There were no statistically significant differences in env gene expression of HERV-W normalized to ACTB in ALL and AML as compared to normal PBL. CONCLUSION: High normalized expression of the env gene of HERV-K in AML strongly suggests a possible contribution of this gene in the pathogenesis of AML.

Polymorphic variant at the IL2 region is associated with type 1 diabetes and may affect serum levels of interleukin-2.

Polymorphic variants at the interleukin-2 (IL2) locus affect the risk of several autoimmune disorders. Our aim was to evaluate the association of the four IL2 polymorphisms (rs6822844, rs6534349, rs2069762 and rs3136534) with type 1 diabetes (T1D) in the Polish population, and to correlate them with the serum interleukin-2 levels. 543 unrelated T1D patients and 706 healthy control subjects were enrolled. The minor T allele at rs6822844 was significantly less frequent in T1D compared to controls (p = 0.002; OR 0.71; 95 % CI 0.571-0.880). Likewise, the frequency of the TT genotype was decreased among the affected individuals (p = 0.007). In healthy subjects, stratification according to the rs6822844 genotype revealed significant differences in circulating interleukin-2 (p = 0.037) with the highest levels in TT protective genotypes. Three other IL2 polymorphisms did not display significant differences in allele and genotype distribution. In conclusion, the rs6822844 variant is associated with T1D and may play a functional role, or reflect the influence of another causative genetic variant in linkage disequilibrium.

Amiodarone-induced thyrotoxicosis in a case of Eisenmenger's syndrome.

Eisenmenger's syndrome is a condition due to any congenital heart defect with an intracardiac left-to-right communication that leads to pulmonary hypertension with reversed right-to-left blood flow and secondary cyanosis. The main complications of Eisenmenger's syndrome are heart failure and arrhythmias. Amiodarone, the drug of choice for arrhythmia treatment in such patients, can cause a number of complications, including amiodarone induced thyrotoxicosis (AIT). Hereby, we present a 41-year-old patient with Eisenmenger's syndrome who developed AIT and was successfully treated with radioactive iodine therapy. The patient had an accompanying heart failure and had been treated with amiodarone due to chronic atrial fibrillation. Twenty months later he developed an AIT for which was treated with 814 MBq (22 mCi) radioactive iodine. Since 7 weeks later only a slight decline in thyroid hormones was observed, the patient was received a transient treatment with methimazole, which had to be withdrawn soon due to severe leucopenia. Because of the need to maintain amiodarone, a second ablative radioactive iodine dose was administered leading to complete clinical remission. In conclusion, this case demonstrates that even though amiodarone reduces iodine uptake to a very low level, the therapy with radioactive iodine can be still effective if it is given in a repeated dose to patients who require continuation of amiodarone.

Assessment of steroid enzymes action in children and adolescents with obesity.

Rising prevalence of obesity has become an important impulse to investigate basic mechanisms involved in regulating the energy balance. It is widely accepted that steroids are potent factors affecting glucose, fat, and protein metabolism. Our study was aimed to analyze differences in the total amount of selected enzymes implicated in steroid metabolism in a group of children suffering from obesity and those with normal weight, further subdivided according to sex and pubertal stage. Data were obtained from 187 Caucasian children and adolescents, including 113 patients (63 girls, 50 boys) with obesity and 74 (34 girls, 40 boys) normal weight volunteers. Standard clinical examinations were performed in both groups. To evaluate the impact of puberty, preadolescent children and those with advanced puberty were assessed separately. Urine steroid excretion profiles were analyzed using gas chromatography/mass spectrometry method. Children with obesity revealed several changes in in the total amount of steroid enzymes as assessed by the relevant metabolite proportions, compared to their norm weight peers. Girls showed a significant increase in the activity of 11ßHSD1, while boys demonstrated a relevant elevation in 20αHSD action. Regardless of sex, children with obesity showed an increase in the activity of 5ß-reductase + 3αHSD complex and a decrease in the involvement of 11ßOH-lase. The effect is attenuated when consider pre- and pubertal subgroups. We hypothesize that changes in the activity levels of selected enzymes may be a compensatory mechanism to limit the glucocorticoid exposure of key target tissues as well as to improve metabolic control and reduce long-term complications of obesity.

The Impact of Obesity on the Excretion of Steroid Metabolites in Boys and Girls: A Comparison with Normal-Weight Children.

Obesity in childhood is associated with several steroid changes, which result from excess body mass. The aim of this study was to evaluate steroid metabolism in children with obesity compared with those with normal weight, especially in relation to sex and puberty progress. We analyzed the clinical data of 191 children, aged between 5 and 18 years, with 115 affected (64 girls and 51 boys) and 76 unaffected (35 girls and 41 boys) by obesity. Routine clinical assessment and pubertal stage evaluation based upon Tanner's scale were performed. In addition, to evaluate the impact of puberty, children with pre-adolescence and advanced puberty were divided into separate subgroups. Then, 24 h urine steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Significant differences in the excretion of steroid metabolites were found between normal weight children and children with obesity, especially in the prepubertal cohort. In this group, we observed enhanced activity in all the pathways of adrenal steroidogenesis. Raised excretion of mineralocorticoid derivatives such as tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, and 5α-tetrahydrocorticosterone supported increased activity of this track. No significant differences were detected in the excreted free forms of cortisol and cortisone, while the excretion of their characteristic tetrahydro-derivatives was different. In pre-adolescent children with obesity, α-cortol and especially α-cortolone appeared to be excreted more abundantly than ß-cortol or ß-cortolone. Furthermore, in children with obesity, we observed elevated androgen excretion with an enhanced backdoor pathway. As puberty progressed, remarkable reduction in the differences between adolescents with and without obesity was demonstrated.

Changes of androgen and corticosterone metabolites excretion and conversion in cystic fibrosis.

Cystic fibrosis (CF) is a life-threatening inherited disease related to a mutation in the CFTR gene, that leads to serious health complications such as chronic pulmonary infections, pancreatic insufficiency, dysfunction of the sweat glands and reproductive system. For the first time, we have described the profile of corticosterone and androgen metabolites in urine, as well as the activity of enzymes involved in steroid genesis and metabolism in people with CF, using gas chromatography/mass spectrometry. A significant reduction in the excretion of most of the measured metabolites in CF was found. These differences were observed in the group of progestagen metabolites, as well as among metabolites of corticosterone and androgens. We revealed higher activities of 17ß-hydroxysteroid dehydrogenase and 17,20-lyase in the Δ4 pathway compared with controls, what can promote the androgen synthesis through the backdoor androgen pathway. We have also found the increased conversion activity of 11-oxyganated steroids by 5a-reductase in backdoor pathway. Levels of the most potent and vital androgens (testosterone and dihydrotestosterone) are comparable in both groups. However, the excretion of dehydroepiandrosterone was lower in CF. Decreased cholesterol lipoprotein levels may contribute to limited intracellular cholesterol supply and reduced adrenal steroidogenesis in CF individuals. Changes in the activity of some steroidogenesis enzymes may suggest the presence of some peripheral adaptive mechanisms in CF to maintain androgen balance in the body despite the limited sufficiency of secretion by the adrenal cortex.

Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison's disease.

Since individuals with Addison's disease (AD) present considerable co-occurrence of additional autoimmune conditions, clustering of autoimmunity was also predicted among their relatives. The study was aimed to assess circulating autoantibodies in first-degree relatives of patients with AD and to correlate them with the established genetic risk factors (PTPN22 rs2476601, CTLA4 rs231775, and BACH2 rs3757247). Antibodies were evaluated using validated commercial assays, and genotyping was performed using TaqMan chemistry. The studied cohort comprised 112 female and 75 male relatives. Circulating autoantibodies were found in 69 relatives (36.9%). Thyroid autoantibodies, that is antibodies to thyroid peroxidase (aTPO) and thyroglobulin (aTg), were detectable in 25.1 and 17.1% relatives, respectively. Antibodies to 21-hydroxylase (a21OH) were found in 5.8% individuals, and beta cell-specific antibodies to ZnT8, GAD, and IA2 were found in 7.5, 8.0, and 2.7%, respectively. The prevalence of a21OH (P = 0.0075; odds ratio (OR) 7.68; 95% CI 1.903-36.0), aTPO (P < 0.0001; OR 3.85; 95% CI 1.873-7.495), and aTg (P < 0.0001; OR 7.73; 95% CI 3.112-19.65), as well as aGAD (P = 0.0303; OR 3.38; 95% CI 1.180-9.123) and aZnT8 (P = 0.032; OR 6.40; 95% CI 1.846-21.91), was significantly increased in carriers of rs2476601 T allele. Moreover, T allele appeared to be a risk factor for multiple circulating autoantibody specificities (P = 0.0009; OR 5.79; 95% CI 1.962-15.81). None of the studied autoantibodies demonstrated significant association with rs231775 in CTLA4 (P > 0.05), and only weak association was detected between BACH2 rs3757247 and circulating aTPO (P = 0.0336; OR 2.12; 95%CI 1.019-4.228). In conclusion, first-degree relatives of patients with AD, carriers of the PTPN22 rs2476601 T allele, are at particular risk of developing autoantibodies to endocrine antigens.

Alteration in glucocorticoids secretion and metabolism in patients affected by cystic fibrosis.

Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11ß-hydroxysteroid dehydrogenase type 2, 5α- and 5ß-reductases. In contrast, the activity of 11ß-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11ß-hydroxyandrosterone/11ß-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11ßHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.

Historical and cultural aspects of obesity: From a symbol of wealth and prosperity to the epidemic of the 21st century.

World Health Organization defines obesity as abnormal or excess adipose tissue accumulation. Nowadays, this condition is a serious threat to the public health in most countries around the world. Obesity adversely affects physical, mental, and in most cultures, social well-being. However, throughout the ages-from ancient times to the 21st century-this condition has been subject to various interpretations. As a matter of fact, obesity has not always been regarded as a disease. For many decades, excessive body weight has been considered rather a symbol of health. It was a marker of wealth and prosperity, as well as a sign of high social status. The centuries that passed on the development of science and medicine have gradually changed its face, but significant progress in understanding the causes and consequences of obesity has been made in the last 30 years. This paper presents the historical outline of obesity and its treatment from ancient times to the present-from its affirmation to the epidemic in the late 20th and 21st century.

[Metabolic assessment of hydrocortisone replacement therapy in patients with primary adrenocortical insufficiency]. / Ocena metaboliczna terapii substytucyjnej hydrokortyzonem u pacjentów z pierwotna niedoczynnoscia kory nadnerczy.

Primary adrenocortical insufficiency (Addison's disease) requires lifelong steroid substitution. Although the patients are both at risk of under-replacement and excessive glucocorticoid exposure, there is no consensus on monitoring this therapy. The aim of the study was to assess the substitution therapy in Addison's disease in regard to metabolic balance, glycaemic effects and bone mineral density. Seventy two subjects with primary adrenal insufficiency (52 women, 20 men) were evaluated. Mean disease duration was 15.6 years. All patients were supplemented with hydrocortisone (10-60 mg/day), 45 also used fludrocortisone, and 8 - dehydroepiandrosterone. The patients underwent medical examination, assessment of glycaemia and electrolyte parameters, and hormonal analyses. Bone mineral density was evaluated in 65 individuals. Mean blood pressure in patients was 117/74 mmHg and positively correlated with age (p < 0.001). No correlation was found between the daily hydrocortisone dose and blood pressure nor electrolyte parameters. Mean morning serum cortisol before hydrocortisone administration was 27 +/- 42 nmol/l, 2 hours later 904 +/- 263 nmol/l, 222 +/- 226 nmol/l before the afternoon dose, and 219 +/- 192 nmol/l around 22.00. Mean 24h urinary cortisol excretion was 521.5 +/- 387 nmol, and morning plasma ACTH was 398.9 +/- 423 pg/ml. Fasting serum glucose was 83.6 +/- 12.6 mg/dl. Fasting glycaemia and insulinaemia did not correlate with hydrocortisone dose but did present a positive correlation with body mass and age. Sixteen patients were diagnosed with osteoporosis in the lumbar spine, and 6 women--in femoral neck. Bone mineral density correlated positively with serum DHEA-S, and negatively with the patient's age, duration of the Addison's disease and total steroid dose administered during the therapy. In conclusion, the steroid substitution in Addison's disease requires individually tailored dosage and adequate monitoring. The factors which may potentially contribute to the development of adverse effects of the glucocorticoid over-supplementation are age, duration of the Addison's disease and total administered steroid dose.