Prevalence of malnutrition and obesity among cystic fibrosis patients.

BACKGROUND: Optimal nutritional status (NS) in cystic fibrosis (CF) is associated with better lung function and increased overall survival. This study estimated the prevalence of malnutrition and obesity among CF patients in a tertiary center. METHODS: In a cross-sectional study of 68 CF patients (33 female; 37 children/adolescents) weight, height, body composition, respiratory function (% of the predicted forced expiratory volume in 1 s; FEV1%pred ) and serum lipids were measured; body mass index (BMI), BMI standard deviation score (BMI-SDS) and BMI percentiles were calculated; Pseudomonas colonization, pancreatic insufficiency, diabetes mellitus (CFDM), liver disease (CFLD) and genotype were recorded; NS was classified according to the 2005 Cystic Fibrosis Foundation (CFF) criteria. Frequency distributions and associations between anthropometric and clinical parameters (univariate/multivariate) were calculated. RESULTS: Mean age (±SD) was 19.81 ± 8.98 years. Regarding NS: 22.1% were malnourished, 13.2% overweight/obese and 29.4% had optimal NS. Pancreatic function (PF), Pseudomonas colonization, CFDM, CFLD and genotype differed significantly among the three groups. FEV1%pred was significantly higher among overweight/obese patients and correlated positively with anthropometric characteristics as well as serum cholesterol and negatively with age. BMI-SDS was associated with PF, FEV1%pred and CFDM. Among overweight/obese patients 89.9% had adequate PF and 66.7% carried mutations other than F508del. No patient had any traits of metabolic syndrome. CONCLUSIONS: Despite appropriate management only one-third of the present patients had optimal NS. One-fourth were malnourished and a significant percentage were overweight/obese. The latter were mostly carriers of mutations other than F508del and had better pulmonary function. CF patients require intensive monitoring for both malnutrition and overweight/obesity.

Adiponectin gene polymorphisms in obese Greek youth.

We investigated single nucleotide polymorphisms 45T --> G and 276G --> T of the adiponectin gene in 48 obese Greek children and adolescents (3.58-16.25 years old) and examined their association with adiponectin levels and insulin resistance (IR), estimated with HOMA-IR, AUC(insulin) and WBISI. The polymorphisms were: 45T/G in 13/48 (27%) and 45G/G in 2 (4%) individuals; 276G/T in 21/41 (51%) and 276T/T in 3 (8%) individuals. Adiponectin in carriers of one or two G-alleles at position 45 was comparable to 45T/T (10.11 +/- 6.19 vs 8.03 +/- 4.96 microg/ml). Adiponectin in carriers of one or two T-alleles at position 276 was comparable to 276G/G (9.73 +/- 5.19 vs 7.77 +/- 5.65 microg/ml). SNP 45T --> G was not associated with IR. SNP276G --> T was associated with decreased risk for IR (OR = 3.05, 95% CI = 1.2384-11.13). In conclusion, SNPs 45T --> G and 276G --> T are common in obese young Greeks. SNP276G --> T might be protective against IR.

Rhabdomyolysis, renal failure, pericardial effusion, and acquired von Willebrand disease resulting from hypothyroidism in a 10-year-old girl.

A 10-year-old girl manifested unexplained muscle aches and high creatine phosphokinase (CPK) concentrations attributed to rhabdomyolysis in association with severe hypothyroidism due to autoimmune thyroiditis. The response to therapy strongly suggested that hypothyroidism was the cause of rhabdomyolysis. Hypothyroidism is a rare cause of rhabdomyolysis. It should always be considered in a patient with muscular symptoms and elevated CPK concentrations. In addition, the patient developed other uncommon manifestations of hypothyroidism such as pericardial effusion, acute renal failure, and acquired von Willebrand disease. After thyroxine replacement, the symptoms and abnormal findings disappeared. The patient was also diagnosed as having celiac disease, which is often associated with autoimmune thyroiditis. Conditions accompanying autoimmune thyroid disease may result from altered thyroid function and from the presence of other autoimmune diseases. The butterfly-shaped thyroid gland has a tremendous impact on metabolism, which may be compared to a phenomenon termed the "Butterfly Effect".

Adiponectin and body composition in cystic fibrosis.

UNLABELLED: The aim of the study was to evaluate adiponectin (AD) serum concentrations in 43 stable CF patients and 27 healthy subjects and to correlate them with their nutritional status. Body Composition (Bioelectrical Impedance), visceral/subcutaneous adipose tissue (VAT-SAT) in CF patients (CT-scan at L4), insulin resistance (HOMA-IR) and AD serum concentrations (ELISA) were studied. CF patients and controls had comparable weight, height, %BF, %FFM, fasting glucose, insulin and insulin resistance. CF patients had significantly lower BMI-SDS. CF males had higher %FFM and total FFM and lower %BF and total BF than females (p<0.001). Serum AD was higher in CF patients than controls (11.53+/-5.37 vs. 9.07+/-4.41 microg/ml) and comparable between females and males. AD was lowest among young malnourished patients (8.06+/-1.85 microg/ml) and highest among young patients with normal nutrition (14.56+/-7.69 microg/ml). Patients with biliary cirrhosis had higher levels than patients with normal liver (10.52+/-5.49 vs. 14.04+/-4.52 mug/ml, p<0.05). AD correlated with %BF, %FFM, FFM (kg) (p<0.05).VAT was significantly increased in malnourished patients. AD was not affected by VAT. CONCLUSIONS: Adiponectin is higher in CF patients than healthy individuals. It is decreased in malnourished young patients and increased in patients with normal nutrition and in patients with liver disease. This may be attributed to the reduced BF and to the energy deficit inherent to the disease.

Adiponectin and insulin resistance in childhood obesity.

OBJECTIVES: To measure adiponectin serum levels in Greek children and adolescents and correlate them with body fat and insulin resistance. PATIENTS AND METHODS: Forty-six obese prepubertal children (19 M, 27 F) and 34 obese adolescents (17 M, 17 F) ages 9.33 +/- 1.57 and 13.6 +/- 1.42 years, respectively, and 43 matched control individuals were studied. Body mass index standard deviation score and percent body fat were measured by bioelectric impedance analysis. Fasting indices of insulin resistance (HOMA-IR and fasting glucose-to-insulin ratio) were calculated for all participants. Indices of insulin resistance derived from oral glucose tolerance tests were estimated in obese participants. Adiponectin was measured by enzyme-linked immunosorbent assay. RESULTS: (MEAN +/- SD):: Adiponectin serum levels were significantly lower in obese participants than in nonobese participants (8.11 +/- 3.80 vs 11.81 +/- 4.98 microg/mL, P < 0.001), in obese children than in nonobese children (8.86 +/- 3.86 vs 13.08 +/- 5.48 microg/mL, P < 0.001), in obese adolescents than in nonobese adolescents (7.04 +/- 3.43 vs 10.47 +/- 4.10 microg/mL, P = 0.002), and in obese adolescent boys than in obese adolescent girls (5.87 +/- 3.52 vs 8.31 +/- 3.16 microg/mL, P = 0.042). There were significant correlations between adiponectin and age, body mass index, body mass index standard deviation score, homeostasis model assessment for insulin resistance, and fasting glucose-to-insulin ratio. Adiponectin correlated with percent body fat after adjustment for sex. Adiponectin correlated significantly with several indices of insulin resistance, such as the areas under the curves for glucose and insulin, whole-body insulin sensitivity index, glucose 120', and insulin 30', in obese participants. CONCLUSIONS: Adiponectin was significantly lower in obese participants than in nonobese participants in general, and it correlated significantly with fasting indices of insulin resistance and with indices derived from oral glucose tolerance tests. It is worthwhile to further investigate the option of applying a simple measurement of serum adiponectin as a screening tool before applying more time-consuming techniques in young obese individuals.

Partial Splenic Embolization: successful treatment of hypersplenism, secondary to biliary cirrhosis and portal hypertension in cystic fibrosis.

Partial Splenic Embolization (PSE) is a non-surgical treatment for hypersplenism. It has been reported only in a limited number of patients with Cystic Fibrosis (CF). We report a case of a female cystic fibrosis patient who developed hypersplenism at the age of 14 and underwent PSE. Long term results over a period of 14 years after the procedure are presented.

Soft tissue inflammation: presenting feature of Crohn's disease in a cystic fibrosis adolescent.

We report Crohn's disease in an adolescent with cystic fibrosis (CF). The patient suffered from recurrent abdominal symptoms, which were attributed to distal intestinal obstruction syndrome (DIOS) until a soft tissue inflammation at the right lumbar region and iliac crest revealed an enterosubcutaneous fistula. The diagnosis of Crohn's disease was confirmed on the basis of radiological, endoscopic and histological findings.

Resting energy expenditure in cystic fibrosis as an indicator of disease severity.

BACKGROUND: An imbalance of energy expenditure has been reported in Cystic Fibrosis (CF). High-energy diets, in combination with pancreatic enzymes, do not always compensate for energy requirements. The aim of this study was to investigate the relation between Resting Energy Expenditure (REE) and disease severity in CF. METHODS: REE was measured with indirect calorimetry in a group of 38 clinically stable CF patients (32 with pancreatic insufficiency and 6 with pancreatic sufficiency). Correlations between REE and pulmonary function as well as clinical status were studied. RESULTS: Increased REE expressed as a percentage of predicted (REE%) was demonstrated in pancreatic insufficient CF patients (PI) (113.3+/-2.5%), as compared to pancreatic sufficient (98.9+/-2.5%) and healthy subjects. The elevated REE% in the PI group was not affected by gender and exhibited a strong correlation with the clinical status of the patients (r=-0.641). CONCLUSIONS: Our data analysis supports the argument that the percentage of predicted REE is an objective indicator of disease severity and progression as well as energy requirements in the assessment of CF patients.

Ghrelin and leptin levels in young adults with cystic fibrosis: relationship with body fat.

BACKGROUND: Ghrelin and leptin are hormones implicated in energy balance coordination and body weight regulation. There are conflicting data regarding the levels and role of leptin while ghrelin has not been studied in CF. The aim of this study was to investigate fasting serum ghrelin and leptin levels in CF adolescents as compared to healthy controls and analyze their association with body fat. METHODS: Fourteen CF adolescents having pancreatic insufficiency and twenty healthy adolescents were enrolled in the study. Diabetic patients were excluded. In all participants' height, weight, body mass index (BMI) and body fat % (BF %) were estimated. Ghrelin and leptin levels were determined after an overnight fast. RESULTS: Weight, BMI and BF% were significantly lower in CF adolescents than those of controls. Fasting leptin levels in CF were significantly higher in CF patients (p=0.030), compared to controls and significantly lower in CF males as compared to CF females (p=0.01). Fasting ghrelin levels were significantly lower in CF males as compared to male controls (p<0.001) and comparable in females. CONCLUSIONS: As the overall clinical outcome of CF patients is related to the nutritional status and body weight, the role of ghrelin and leptin in these patients needs to be elucidated.

Ghrelin serum levels during oral glucose tolerance test in prepubertal obese children with insulin resistance.

BACKGROUND: An involvement of ghrelin in glucose metabolism has been suggested; nevertheless, the relationship between ghrelin and insulin resistance (IR) remains unclear. AIMS: 1. To investigate the effect of glucose loading on ghrelin in prepubertal obese children with IR. 2. To assess possible correlations between IR and changes in circulating ghrelin. PATIENTS AND METHODS: Twenty prepubertal obese, insulin-resistant and 18 age- and sex-matched lean children were studied. Fasting glucose, insulin and ghrelin levels were measured. In the obese group, measurements were repeated during an OGTT. RESULTS: Ghrelin levels were decreased at 60 min, but thereafter increased to baseline values. The fall in circulating ghrelin was negatively correlated with IR and the respective rise in insulin levels. CONCLUSIONS: In prepubertal, insulin-resistant obese children, ghrelin is significantly suppressed shortly after glucose intake. It is possible that the above effect is attenuated by IR and the resultant increase in insulin levels.

Ghrelin and leptin levels in obese adolescents. Relationship with body fat and insulin resistance.

OBJECTIVE: Ghrelin and leptin levels are influenced by body fat (BF%), pubertal stage and possibly insulin resistance (IR). The aim of our study was: 1) To compare fasting ghrelin and leptin levels between obese and non-obese, adolescents, 2) to investigate possible correlations of these hormones with BF %, as well as IR. DESIGN: Twenty obese insulin resistant (IR) adolescents, twenty obese non IR (NIR) and fifteen healthy non-obese, age-matched adolescents were studied. In all participants, height, weight, body mass index (BMI) and BF % were measured. Fasting glucose, insulin, ghrelin and leptin levels were determined. IR was assessed using HOMA-IR index. RESULTS: BMI, BF %, insulin and HOMA-IR values were positively correlated with leptin and negatively with ghrelin levels. A negative correlation between circulating leptin and ghrelin levels was found. A suggestive positive correlation between leptin levels and BF %, independent of BMI, was also observed (P=0.075). Ghrelin levels were significantly correlated with insulin levels and HOMA-IR, independent of BMI (P=0.077). CONCLUSIONS: Obesity and IR may play an important role in the release of ghrelin as well as in the negative correlation between ghrelin and leptin.

Subclinical exocrine pancreatic dysfunction resulting from decreased cholecystokinin secretion in the presence of intestinal villous atrophy.

UNLABELLED: The aim of this study was to evaluate the concept that pancreatic dysfunction in patients having gluten sensitivity (celiac disease [CD]) or cow's milk protein enteropathy (CMPE) may result from the lack of pancreatic enzyme stimulation in the absence or decrease of cholecystokinin (CCK) secretion caused by villous atrophy. PATIENTS AND METHODS: The following parameters were measured: plasma CCK in response to a fatty meal and human pancreatic fecal elastase in 24 patients with CD while on gluten-free diet and after gluten provocation and in 12 patients with CMPE at diagnosis and after a 6-month period of cow's milk-free diet. Intestinal mucosa morphology was examined by small bowel biopsy. Sixty-three controls having no organic gastrointestinal problems were investigated once at the time of diagnostic evaluation. RESULTS: Fasting CCK, obtained at a time when patients with CD or CMPE had normal intestinal mucosa, was significantly different from postprandial and comparable to that of the control group. Fasting CCK obtained from patients with villous atrophy was also statistically different, but not significantly, from the postprandial. Fasting and postprandial plasma CCK and fecal pancreatic elastase values from patients having normal intestinal mucosa were significantly higher than those obtained from patients with villous atrophy. Significant correlation of intestinal mucosa morphology and CCK with fecal elastase concentration was documented. CONCLUSION: Exocrine pancreatic dysfunction in individuals having villous atrophy may be the consequence of decreased CCK secretion. Cholecystokinin and pancreatic secretion is restored to normal, with intestinal mucosa regeneration.

Successful pregnancy and delivery in a young woman with cystic fibrosis and gestational diabetes.

We describe a 23-year-old Delta F508 homozygote cystic fibrosis primigravida. At the onset of gestation, she had mild to moderate pulmonary involvement, exocrine pancreatic insufficiency, focal biliary cirrhosis, satisfactory nutritional status and normal fasting and post-prandial glucose blood levels. At 29 weeks, she developed polyhydramnion and gestational diabetes. At 37 weeks, she was delivered of a live 2,980 g boy by caesarean section under epidural anaesthesia. Insulin was subsequently discontinued and her pulmonary function improved spontaneously. Neither maternal nor neonatal health problems were observed during the 3-month follow-up.

Fecal elastase-1 cut-off levels in the assessment of exocrine pancreatic function in cystic fibrosis.

BACKGROUND: Fecal elastase-1 (E1) test is a sensitive and specific indirect test. However, there are few data on the best cut-off level in the assessment of exocrine pancreatic function in cystic fibrosis (CF). MATERIAL AND METHODS: In 725 CF patients and 243 healthy subjects (HS) from Greece, Russia, Poland and the United Kingdom, E1 concentrations were measured. The best cut-off levels for the discrimination between CF and HS (for whole group as well as for individual countries) were calculated. RESULTS: The best cut-off level for the differentiation between CF pancreatic insufficiency and normal pancreatic function in HS was found to be 184 microg/g of feces. However, some inter-country differences were stated. E1 concentrations in the UK subgroup were significantly lower than those found in Polish and Russian CF patients. E1 concentrations in Greek patients were significantly higher than in the other countries. However, E1 concentrations in Delta F508 homozygotes were very similar in all studied subgroups. IN CONCLUSION: In clinical practice, instead of a single best cut-off level for the E1 test, we suggest using a range of values (160-200 microg/g). The presence of different best cut-off levels within countries is a practical consequence of the different distribution of pancreatic function.

Insulin resistance and hyperinsulinemia in prepubertal obese children.

BACKGROUND: Tissue resistance to insulin has been demonstrated in obese individuals. Pancreatic beta-cells respond to the reduced tissue sensitivity with increased insulin secretion so that glucose homeostasis is maintained. OBJECTIVE: The purpose of this prospective study was to investigate the presence of hyperinsulinemia and insulin resistance in obese children and adolescents. SUBJECTS AND METHODS: Fasting glucose (FG) and insulin (FI) levels and fasting glucose to insulin ratio (FGIR) were measured in 26 obese prepubertal children and 20 obese adolescents, as compared to 20 non-obese prepupertal children and 20 adolescents with normal body weight. Furthermore, obese children and adolescents underwent an oral glucose tolerance test with measurements of glucose and insulin 2 hours post glucose load. RESULTS: In 14/26 (54%) obese prepubertal children and in 16/20 (80%) obese adolescents FI was >24 microU/ml. FGIR was <6 in 23/26 (88%) prepubertal obese children and in all obese adolescents. All non-obese prepubertal children and adolescents had normal FI. However, FGIR was <6 in 6/20 (30%) non-obese prepubertal children and in 15/20 (75%) non-obese adolescents. CONCLUSION: Hyperinsulinemia and insulin resistance are already present in prepubertal obese children. As hyperinsulinemia is a potentially reversible condition and the complications related to it may be prevented, early measurements should be undertaken so that obese children lose body weight before the onset of puberty which may enhance the problem of insulin insensitivity.

Classical phenotype of Laron syndrome in a girl with a heterozygous mutation and heterozygous polymorphism of the growth hormone receptor gene.

We describe here a 19 month-old girl with classical Laron syndrome (LS). Molecular analysis of the GH receptor gene in the patient and her parents was performed. The patient was found to be heterozygous for a mutation in exon 4 (R43X) and heterozygous for a polymorphism in exon 6 (Gly168Gly). Her mother was also heterozygous for R43X but homozygous for the polymorphism. In the father, a heterozygous polymorphism was found. Contrary to previous assumptions that only homozygous patients express the typical phenotype, this patient shows all the classical features of LS, despite being a heterozygote for a pathological defect.

Laron syndrome. First report from Greece.

Laron-type dwarfism is an autosomal recessive disorder caused by deletions or mutations of the growth hormone receptor gene. It is characterized by high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I). Patients are refractory to both endogenous and exogenous GH, and present severe growth retardation and obesity. Therapy with recombinant human insulin-like growth factor-I (rhIGF-I) accelerates linear growth. We describe a 2-year old girl with Laron syndrome, who presented with postnatal growth failure and hypoglycaemic seizures. Her evaluation disclosed high GH values during a glucagon test (peak GH value 170 ng/ml) and very low IGF I value (0.1 ng/ml) with no rise following GH administration. The growth velocity improved considerably with the administration of IGF I. Molecular analysis showed a heterozygous mutation on exon 4 of the GH receptor gene, inherited from the mother, a rather puzzling finding considering the clinical findings in mother and infant. This case constitutes the first report of Laron syndrome from Greece.

Multifollicular ovaries in female adolescents with cystic fibrosis.

OBJECTIVE: To assess hormonal status and morphology of ovaries in cystic fibrosis (CF) adolescents. DESIGN: Prospective study. SETTING: University teaching hospital. PATIENT(S): Female adolescents: 18 with CF and 18 normal. INTERVENTION(S): Transabdominal pelvic ultrasonography and venipuncture. MAIN OUTCOME MEASURE(S): Hormone profile and ultrasound examination of ovaries and uterus. RESULT(S): Levels of LH, LH/FSH, androstenedione, and PRL were significantly higher in the CF adolescents. Levels of sex hormone-binding globulin (SHBG) were significantly lower and had negative correlation with percentage of body fat. Percentage of body fat and body mass index were significantly lower in CF and had significant correlation. Levels of E2, FSH, T, and DHEAS were comparable in the two groups. Ultrasound revealed cysts in eight (44%) of the CF subjects; six of these had LH/FSH >3, and three had been operated for ovarian torsion. Nine out of all of the CF subjects (50%) had DM. No obesity, hirsutism, or acne was observed. The Shwachman score was 87.44 +/- 4.83 and correlated significantly with the percentage of body fat. CONCLUSION(S): Multifollicular ovaries were frequent in CF adolescents. Hormone changes characteristic of polycystic ovary syndrome were detected. The low T levels, despite low SHBG, and the absence of hirsutism or acne may be a result of a lower percentage of body fat, disturbances at the pilosebaceous-adipocyte endocrine unit, or mechanical or other causes.

Longitudinal follow-up of exocrine pancreatic function in pancreatic sufficient cystic fibrosis patients using the fecal elastase-1 test.

BACKGROUND: A progressive decline in pancreatic function is possible in cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. The secretin-cholecystokinin test is invasive and not acceptable as a repeatable procedure for children. Steatorrhea, conversely, has low sensitivity. Therefore, the aim of the present study was to evaluate the usefulness of the noninvasive fecal elastase-1 (E1) test for the longitudinal assessment of exocrine pancreatic function (EPF) in pancreatic-sufficient (PS) CF patients. METHODS: One hundred eighty-four CF patients were included in the study. In all subjects, E1 concentrations and fecal fat excretion were measured. PS patients were followed for 5 years. RESULTS: At the beginning of the study, 35 (19.0%) CF patients were PS, and 32 (17.4%) had normal E1 concentrations. Longitudinal measurements of E1 concentrations in PS patients with CF demonstrated stable enzyme output in 27 and gradual decrease in 8. The decrease was rapid in five infant patients and gradual in three older patients. The decrease of E1 concentrations preceded the appearance of steatorrhea in all eight subjects. CONCLUSIONS: The decline of EPF in patients with CF appears more frequently during the first months and years of life. However, late PS to pancreatic-insufficient (PI) conversion is also possible. The appearance of maldigestion is preceded by the decrease of fecal E1 concentration. Thus, the fecal E1 test is a helpful screening tool for the longitudinal assessment of declining EPF in PS patients with CF to demonstrate pancreatic deterioration. In suspected patients, fecal fat excretion should be assessed.

Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B).

Wilson disease (WND) is caused by mutations in the ATP7B gene and exhibits substantial allelic heterogeneity. In this study we report the results of molecular analyses of 20 WND families not described previously. When combined with our prior results, the cohort includes 93 index patients from 69 unrelated families. Twenty different mutations accounted for 86% of the WND chromosomes. The most frequent were p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%), and p.I1148T (3%). We also present here a detailed phenotypic assessment for patients whose molecular result was previously reported. Thirty cases were homozygous for 9 different mutations, 13 of which were homozygous for p.H1069Q, and 7 for p.R969Q. Mutations p.H1069Q and p.R969Q appeared to confer a milder disease as patients showed disease onset at a later age, and were associated with milder severity when found in trans with severe mutations. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. WND can be treated by copper-chelation therapy, particularly if the disease is diagnosed before irreversible tissue damage occurs. Our results on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes.