Jerzy Starzyk

Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).

Objective  Mutations within the pituitary‐specific paired‐like homeobox gene PROP1 have been described in 50–100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1.

Screening for congenital hypothyroidism: the value of retesting after four weeks in neonates with low and very low birth weight.

Objectives: Thyroid-stimulating hormone (TSH), normally a reliable screening test for congenital hypothyroidism (CH), may fail to detect cases among infants who have low and very low birth weight. The purpose of this study was to identify neonates with false-negative screening results. Setting: A province in Poland in which 3854 neonates had body weight ≤2500 g, between 1999 and 2001. Methods: TSH levels in blood on filter paper were measured in all neonates between the third and sixth days after birth, but were repeated in low and very low birth weight infants after four weeks of age. Results: The repeat test showed TSH levels ≥ 10 mIU/L in 19 of the 3854 low birth weight neonates. The final diagnosis in these neonates was permanent CH in two, transient CH in five, possible compensated CH in six and transient high TSH in six. Of the 19, 16 (84%) required iodine and/or thyroxine replacement therapy. Conclusions: In neonates with low and very low birth weight, normal TSH levels measured between the third and sixth day of life do not exclude thyroid dysfunction, but a repeat TSH measurement after the fourth week of life identifies the false-negative results. In our data, the prevalence of primary and secondary hypothyroidism (both permanent and transient) was about 0.5%.

Cholecystokinin, glucose dependent insulinotropic peptide and glucagon-like peptide 1 secretion in children with anorexia nervosa and simple obesity

Cholecystokinin (CCK), glucose dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1) regulate satiety as enterogastrons and incretins. They also directly affect the satiety centers. Therefore, these peptides may participate in the pathogenesis of eating disorders. CCK, GIP, and GLP-1 secretion were studied in 13 adolescent girls suffering from simple obesity, 13 girls with anorexia nervosa, and 10 healthy girls. Each girl was subjected to an oral glucose tolerance test (OGTT) and standard meal test. Blood was collected before stimulation and at 15, 30, 60, and 120 min. The concentrations of all peptides were determined by RIA commercial kits. Fasting and postprandial levels of these peptides as well as integrated outputs were measured. High postprandial levels of CCK observed in the girls with anorexia may aggravate the course of this disease by intensifying nausea and vomiting. Low postprandial level of GLP-1 in girls with simple obesity may be responsible for excessive ingestion of food and weaker inhibition of gastric emptying, which also leads to obesity.

A decrease in fasting FGF19 levels is associated with the development of non-alcoholic fatty liver disease in obese adolescents.

Abstract Aim: Fibroblast growth factor 19 (FGF19) is a hormone released from the small intestine; recently, it has emerged as an endocrine regulator of glucose and lipid metabolism. The aim of this study was to investigate the role of FGF19 in the development of nonalcoholic fatty liver disease (NAFLD). Patients: This study included 23 (17 boys) obese adolescents (mean age of 14.1 years) with NAFLD. The control group consisted of 34 (13 boys) obese peers with normal ultrasonographic imaging and normal liver function tests. Methods: The definition of NAFLD was based on clinical criteria: elevated alanine aminotransferase (>35 U/L) and liver steatosis features on ultrasound imaging. Serum FGF19 levels were measured in a fasting blood sample. The definition of insulin resistance was based on the homeostasis model assessment (HOMA) threshold: >2.5. Results: There was a significant difference between mean FGF19 levels in patients with NAFLD and controls (142.2 vs. 206 pg/mL, p=0.04). Mean fasting FGF19 levels were decreased in insulin-resistant patients in comparison with the non-insulin-resistant group (155.0 vs. 221.0 pg/mL, p=0.05). There was an inverse correlation between FGF19 and alanine aminotransferase levels (R=–0.3, p<0.05) and triglycerides (R=–0.27, p<0.05). Conclusion: A decrease in fasting FGF19 is associated with the development of NAFLD in obese adolescents. A decrease in fasting FGF19 levels may be a new important risk factor for NAFLD and the metabolic syndrome in adolescents. Further studies are needed to explain whether exogenous delivery of FGF19 might be therapeutically beneficial.

Suprasellar Arachnoidal Cyst as a Cause of Precocious Puberty - Report of Three Patients and Literature Overview

The authors present three boys--3 years old, 5.8 years old and 10.4 years old--who were diagnosed with isosexual precocious puberty (IPP) triggered by a rare developmental disorder of suprasellar arachnoid cyst (SAC) accompanied by corpus callosum and fornix dysgenesis as well as anterior commissura magna agenesis (patient 1) and empty sella (patients 2, 3). The reason for diagnostic management recommendation was a rapid progression of IPP signs over one year (patients 1, 2) or 6 months (patient 3) prior to hospitalization, these signs having been present but less intense since infancy (patient 1), 4th year of life (patient 2) and approximately 8 years of age (patient 3). Neurological signs (spastic paresis in patient 1, postural tremor in patient 2 and head bobbing and behavioral changes in patient 3), as well as slowly progressing increased head circumference were observed since neonatal period (patient 1), 1 year old (patient 2) and approximately 4 years old (patient 3). None of the patients manifested hypophyseal-hypothalamic axis dysfunction other than IPP prior to and after surgical management. Shunt implantation resulted in gradual resolution of neurological signs in all patients and in patient 3 also in partial normalization of serum testosterone levels and growth rate. Regression of IPP in patients 1 and 2 was achieved by administration of a long-acting GnRH analogue. Our observations are in accord with data reported by other investigators and confirm the often slow, insidious development of subsequent SAC signs, the type and intensity of which differ from patient to patient. We suggest that some of the neuroanatomical anomalies coexisting with SAC may have a common genesis, or they could under certain conditions be an additional trigger for IPP and possibly other hypothalamopituitary dysfunction.

The association of FGF23 levels in obese adolescents with insulin sensitivity.

Abstract Background: The fibroblast growth factor 23 (FGF23) is the most important hormonal regulator of circulating phosphate levels. Apart from this essential role, it may also act as a ‘hormone-like’ factor involved in glucose and lipid metabolism. It is believed to have a potential role in the development of insulin resistance. Aim: The aim of the study was to compare FGF23 levels between two groups of obese adolescents: insulin resistant and non-insulin resistant. Patients: The study included 36 obese, insulin-resistant adolescents (21 boys and 15 girls) of pubertal age (mean age, 13.95 years; Tanner stage IV or V). The control group consisted of 21 obese peers with normal HOMA-IR values. Methods: FGF23 levels were measured in a fasting blood sample by Human Intact FGF-23 ELISA Kit (Immunotopics Inc., San Clemente, CA, USA). A standard oral glucose tolerance test was performed, which assessed fasting and 120 min postload plasma glucose and serum insulin levels; the insulin resistance index HOMA-IR was calculated. The definition of insulin resistance was based on a HOMA-IR threshold set for adolescents (≥3.16). Results: There was a significant inverse correlation between FGF23 levels and HOMA-IR (R=–0.26, p<0.05) in the study group. FGF23 levels were also significantly lower in the study group (9.8 vs. 11.9 pg/mL, p=0.026). Conclusions: In adolescents with simple obesity and insulin resistance, FGF23 levels are lower compared with obese adolescents with normal HOMA-IR.

Entero-insular axis in children with anorexia nervosa.

UNLABELLED Entero-insular axis plays an important role in generating satiety signal. Thus disturbances in this axis may influence the course of anorexia nervosa. The aim of the study was analysis of the function of the hormonal part of the entero-insular axis in girls with anorexia nervosa. Thirteen girls with anorexia nervosa and in 10 healthy girls were studied. Each girl was subjected to oral glucose tolerance test and standard meal test. Blood was collected before stimulation and within 15, 30, 60, and 120 min thereafter. The concentrations of all peptides were determined by radioimmunoassay commercial kits. Fasted and postprandial levels of these peptides as well as integrated outputs were measured. Fasting insulin concentration was significantly higher in the group of girls with anorexia nervosa than in the control group (p<0.03). What more in girls with anorexia the integrated output of insulin was significantly lower in oral glucose tolerance test than after the meal (p<0.001). Also the integrated output of glucagon in both tests was higher in the group of girls with anorexia than in the control group. The mean output of pancreatic polypeptide and cholecystokinin in anorexia group was significantly higher (p<0.001 in both cases) than that in the control group but only after the test meal. The integrated outputs of gastric inhibitory peptide in both tests were significantly higher in anorectic girls than those in the control group (oral glucose tolerance test, p<0.02; meal test, p<0.001), However, mean values of the integrated output of glucagon-like peptide 1 in both tests were significantly higher in the control group than in the girls with anorexia (p<0.001 in each case). Highly significant correlation was found between glucose concentration and the concentrations of insulin, cholecystokinin, and gastric inhibitory peptide in both tests and for the both groups. In the anorectic girls, significant correlation between insulin concentration and the concentration of gastric inhibitory peptide was found after both stimulation tests and between insulin and cholecystokinin after oral glucose only. CONCLUSION the disturbed secretion of the hormones of entero-insular axis after the meal in anorectic girls may have negative influence on the course of anorexia nervosa. This disease has no effect on the incretin function of cholecystokinin, gastric inhibitory peptide and glucagon-like peptide 1.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

Background/Aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5–72.7 (median 16.6) years from 60 kindreds. Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0–20.7) and median volume was 127.6 mm3 (range 7.5–3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

Left Ventricular Diastolic Dysfunction in Adolescents with Type 1 Diabetes Reflects the Long- but Not Short- Term Metabolic Control

ABSTRACT Objective: The aim of this study was to compare the LV morphology and function in adolescents with DM1 and their healthy peers. Subjects and Methods: In 59 DM1 patients (30 girls, 29 boys,aged 14-17 years), and in control group (15 girls, 15 boys) LV was assessed by M-mode, 2D and Doppler echocardiography. The metabolic control was assessed in the long- (mean HbA1c value for the entire treatment period-HbA1c1), medium- (mean HbA1c for the past two pre-study years-HbA1c2), and short-term (HbA1c on the day of the study- HbA1c3). Results: Diabetic patients presented an increase of IRT (0.062 vs. 0.056 s,p<0.05 in boys, and 0.062 vs. 0.056 s,p<0.05 in girls), A wave (56.1 vs. 53.95 cm/s in boys, and 60.3 vs. 58 cm/s in girls), and deceleration time values (0.16 vs. 0.15 s in boys, and 0.17 vs. 0.15 s in girls), decrease of E wave (97.35 vs. 104.9 cm/s in boys, and 99.67 vs. 101.8 cm/s in girls), as well as the E/A ratio (1.79 vs. 2.0 in boys, and 1.7 vs. 1.78 in girls). The systolic function was normal. In girls there was a correlation between IRT and HbA1c1 and HbA1c2 (r=0.42,r=0.46,p<0.05); between the A wave and HbA1c2 (r=0.46,p<0.05); between LV posterior wall systolic dimension and HbA1c1, HbA1c2 (r=0.45,r=0.41,p<0.05), and in boys between the A wave and HbA1c1 and HbA1c2 (r=0.48,p<0.01;r=0.37, p<0.05). Conclusions: Pubertal patients with DM1 demonstrate discrete impairment of the diastolic function beside normal systolic function of the LV. Further investigations are needed to assess the value of this observation. It seems that LV diastolic dysfunction in girls depends on the degree of insulin resistance and DM1 duration, and similarly as in boys, on the long-term metabolic control.

Metabolic control and its variability are major risk factors for microalbuminuria in children with type 1 diabetes

INTRODUCTION To assess in a prospective study the course and the predictors of microalbuminuria in children and adolescents with type 1 diabetes. MATERIAL AND METHODS 438 children and adolescents who developed diabetes in the years 1985-2004 were followed for 9.2 ± 3.4 years from the diagnosis. Microalbuminuria was assessed on the basis of timed overnight urine collections performed once per year. Variability of glycated haemoglobin was expressed as a coefficient of variation (%) calculated by dividing standard deviation (adjusted for the number of measurements) by mean of HbA1c. RESULTS Microalbuminuria was noted in 99 patients (22.6%) after 8.27 ± 3.3 years of diabetes. In 29 individuals (6.6%), microalbuminuria was persistent. The prevalence of microalbuminuria was not dependent on the period of diabetes diagnosis. During followup, 17 (58.6%) patients with persistent MA reverted to normoalbuminuria. Children without any episodes of microalbuminuria had significantly lower HbA1c variability (8.44%; 95% CI 7.81-9.08%) than those with one (10.28% 95% CI 9.10-11.47%; p = 0.007). The difference of HbA1c variability between patients with and without microalbuminuria persisted after correction by mean HbA1c (p = 0.04). Risk factors for ever developing microalbuminuria during the observation period in multivariate analysis included: mean HbA1c (HR [95% CI]: 1.17 [1.00-1.37; p = 0.05]) and its variability (1.04 [1.00-1.07]; p = 0.05), insulin dose (HR per 0.1 unit*kg- 1*day-1: 0.87 [0.79-0.96]; p = 0.005), presence of arterial hypertension (1.63 [1.07-2.49]; p = 0.02), and age at onset of diabetes (1.15 [1.08-1.21]; p < 0.0001). CONCLUSIONS Children who develop microalbuminuria are characterised by poorer and more variable metabolic control, hinting at the importance of interventions aimed at both improvement and stabilisation of HbA1c levels.