Acid sphingomyelinase-deficient Niemann-Pick disease: novel findings in a Greek child.

Niemann-Pick Disease (NPD) is a heterogeneous group of autosomal recessive disorders characterized by progressive accumulation of sphingomyelin and cholesterol in lysosomes. Six types of NPD have been described based on clinical presentation and involved organs. The primary defect in NPD types A and B is a deficiency of lysosomal acid sphingomyelinase (ASM). We present a case of a 5-year-old boy with type B NPD who had severe clinical manifestations, including heart involvement. He was first admitted to the hospital at 2 months because of vomiting, refusal to feed, lethargy, hepatomegaly and mild transaminasaemia. Liver biopsy at 12 months showed lipid accumulation and fibrosis. Investigations for lysosomal storage disorders revealed increased plasma chitotriosidase (549 nmol/h per ml, normal value 0-150). At 18 months, no detectable ASM activity was observed in cultured fibroblasts (normal range 23-226 nmol/h per mg protein) confirming NPD B. Pulmonary involvement was detected with high-resolution computerized tomography which revealed reticulonodular infiltrations and thickening of the interlobular septa. At 2 years growth retardation and kyphosis were noted. At 2.5 years he manifested neurodevelopment regression, indicating CNS involvement. Cardiac involvement (grade III mitral valve insufficiency) developed at 4 years and heart failure at 5 years. Genetic analysis revealed two mutations: a H421Y mutation that is common in Saudi Arabian and Turkish patients, and a W32X mutation, which has been found in other Mediterranean patients.

Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic Fibrosis Study Group.

BACKGROUND: More data on the efficacy and safety of ciprofloxacin in pediatric cystic fibrosis patients are needed. METHODS: One hundred eight pediatric cystic fibrosis patients (ages 5 to 17 years) with acute bronchopulmonary exacerbations entered a randomized multicenter trial designed to compare the safety and efficacy of antipseudomonas therapy with oral ciprofloxacin (15 mg/kg twice daily; maximum dosage 750 mg twice daily) or intravenous ceftazidime plus tobramycin (CAZ/TM) for 14 days. RESULTS: Clinical improvement was observed in 93% of patients treated with oral ciprofloxacin and in 96% of those receiving parenteral therapy. Transient suppression of Pseudomonas aeruginosa was achieved in 63% of patients at the end of the course of iv CAZ/TM therapy and in 24% receiving ciprofloxacin. Ultrasound examination and nuclear magnetic resonance imaging scans showed no evidence of cartilage toxicity in any of the ciprofloxacin-treated patients. Musculoskeletal adverse events were reported with similar frequency in the two groups of patients (7% in the group receiving ciprofloxacin therapy and 11% in the IV CAZ/TM group). The only sustained musculoskeletal symptom was a case of synovitis in a patient receiving parenteral CAZ/TM. CONCLUSION: Ciprofloxacin thus appears to be safe and effective for use in young patients with bronchopulmonary exacerbation of cystic fibrosis.

Pancreatic polypeptide in cystic fibrosis.

Patients with cystic fibrosis (CF) and their normal siblings and parents were studied for protein meal-stimulated pancreatic polypeptide (PP) secretion. Patients with CF who had exocrine pancreatic insufficiency did not respond to a protein meal, whereas patients with CF and normal pancreatic function presented relatively well-preserved basal and elevated postmeal PP levels. The siblings responded with relatively lower PP levels compared with the control subjects. Plasma insulin levels were also investigated, and showed sluggish initial-phase but relatively well-preserved insulin responses in the patients with CF. Immunocytochemical and morphometric studies were made of pancreata obtained at autopsy from patients with CF. In the patients younger than 7 years of age, well-preserved islet tissue was disclosed by islet-area morphometry with normal and/or below-normal PP cell counts, whereas patients older than 9 years had relatively less insulin-containing islet tissue and scanty PP cells. Absent PP secretory response in patients with CF who had exocrine pancreatic insufficiency may suggest defects in the PP secretory mechanism. Abnormal PP secretion may be used as an indirect index of pancreatic damage in CF.

Glucose-6-phosphate dehydrogenase deficiency-induced hemolysis in newly diagnosed diabetic monozygotic twins.

A pair of monozygotic male twins are described who manifested hemolysis at the concurrent onset of diabetes type 1. Hemolysis appeared progressively following the correction of hyperglycemia and ketoacidosis (one twin). It was found to be related to unknown glucose 6-phosphate dehydrogenase (G-6-PD) deficiency. Other causes of hemolysis such as drugs or bacterial infection were excluded. The fall in glucose availability after the correction of hyperglycemia is proposed as a possible explanation for hemolysis.

Osteopenia in children and adolescents with hyperprolactinemia.

Three patients with hyperprolactinemia due to pituitary adenomas (two patients) or empty sella (one patient) and osteopenia are described. Their ages at presentation ranged from 8 to 17 years. Each patient was treated with cabergoline. Serum prolactin levels became normal in all patients within one month. Bone density and pubertal stage improved after 12 months of treatment.

Islet autoantibodies and insulin dependent diabetes mellitus in cystic fibrosis.

Cystic fibrosis-related diabetes mellitus (CF-DM) is thought to be secondary to beta-cell destruction by fibrous tissue replacing the exocrine pancreas. The aim of this study was to investigate the hypothesis that other factors may also be responsible. Glutamic acid decarboxylase (GAD) and islet cell (IA-2) antibodies were measured by quantitative ELISA in a group of patients with CF (n=30) in comparison to a group of newly diagnosed DM type 1 (IDDM) patients (n=30) and normal subjects (n=30). GAD antibodies were positive (>32 ng/ml) in 50% of the CF, 93% of the IDDM and 0% of the control group. IA-2 antibodies were detected (>0.9 U/ml) in 40% of the CF, 93% of the IDDM and 0% of the control group. Among the fifteen CF patients with positive GAD and IA-2 antibodies, four already had IDDM and another five abnormally low (<45 mU/l) first phase insulin response (FPIR) indicating a prediabetic state. We conclude that factors other than mechanical may be involved in the development of CFDM. The presence of autoantibodies predicting IDDM supports the hypothesis that CF-DM may have a multifactorial pathogenesis.

Complications associated with total parenteral nutrition in infants with short bowel syndrome.

The use of total parenteral nutrition (TPN) in five out of six infants with short bowel syndrome (SBS) adaptation permitted enteral nutrition. The duration of TPN depended on the extent of the resection, whether it was proximal or distal, and the adaptation of the residual gut. Residual bowel measuring 10 cm required prolonged TPN in the sixth infant and was not compatible with survival. Catheter-related complications were infection, malposition and dislodgement of the catheter. Metabolic complications were easily controlled by regulating the concentration of the infusate and the rate of the infusion. Osteopenia was common in prolonged TPN and was corrected with vitamin D supplementation. Cholestasis was the most common complication. It was demonstrated with elevation of gamma-glutamyl-transpeptidase levels which became evident as early as six weeks after the introduction of TPN. Serum bilirubin and transaminase elevations were later manifestations. One infant died of hepatic decompensation. Late morphological manifestations were those of cholestatic changes with fibrosis. The biochemical abnormalities of cholestasis were reversible provided TPN was discontinued at an early stage.

Quality of life of children and adolescents with diabetes of Northern Greek origin.

AIM: To culturally adapt the diabetes- specific quality of life (QOL) instrument PedsQL 3.0 Diabetes Module (DM) and the generic QOL instrument PedsQL 4.0 Generic Core Scales (GCS) to the population of Greek diabetic children. Also, to evaluate QOL in youths with type 1 diabetes, compare it with that of healthy youths, and identify relationships between QOL and metabolic control and intensity of treatment. PATIENTS AND METHODS: Eighty nine (89) children and adolescents with type I diabetes and 89 without diabetes, all with their parents (2-18 years of age, diabetes duration>6 months) completed the Greek GCS. Those with diabetes also completed the Greek DM. RESULTS: Cronbach alpha coefficient of child and parent report of both instruments, in general approached 0.70, indicating their internal consistency reliability. Both instruments demonstrated positive intercorrelations with their total scores and subscales of DM demonstrated positive intercorrelations with total score of the generic instrument, supporting the validity of both instruments for the evaluation of QOL of Greek diabetic children. No statistically important differences were found among patient and parent report of diabetes and control group in both instruments. Exception was "Social functioning" in which children with diabetes reported better QOL. Growing age, female gender, large BMI, poor metabolic control and intensity of treatment did not influence QOL of children with diabetes. CONCLUSIONS: Greek PedsQL GCS and DM have sufficient acceptability, reliability and validity so as to be used for the purposes of a comparative study. Youth with diabetes reported similar QOL with non-diabetic youth of the same age and socioeconomic status.

Effect of exocrine pancreatic function on resting energy expenditure in cystic fibrosis.

AIM: To prove the hypothesis that exocrine pancreatic function determines resting energy expenditure (REE) in cystic fibrosis (CF). METHOD: Thirty-eight CF individuals, 9-34 (19.98 +/- 1.0) years, were divided into three groups: Six pancreatic sufficient patients (PS; group A), 21 pancreatic insufficient patients (PI), whose pulmonary function was comparable to that of group A (group B1) and 11 PI patients, whose pulmonary function was significantly worse than that of group A (group B2). REE was estimated by indirect calorimetry. Predicted REE was based on Schofield equations. Measured REE was expressed as % of the predicted. BMI, BMI z-scores, serum albumin, cholesterol and triglycerides levels were related to REE. Results were expressed as mean +/- standard error. RESULTS: Groups B1 and B2 had significantly higher REE% (111.7 +/- 2.75% and 119.94 +/- 3.8, respectively) as opposed to group A (98.9 +/- 3.81%; p = 0.022 and 0.035, respectively) whose REE% was similar to that predicted. REE% between group B1 and B2 was not statistically significant. In groups A, B1 and B, mean FEV1% was 86.33 +/- 10.1%, 90.24 +/- 4.39%, 44.54 +/- 3.47%, respectively, mean BMI was 25.6 +/- 2.06, 19.48 +/- 0.64 and 20.09 +/- 8.8, respectively, BMI z-scores were 0.75 +/- 0.51, -0.52 +/- 0.24 and -1.07 +/- 0.37, respectively. Significant correlation was demonstrated between REE%, BMI z-scores and cholesterol levels in group A. CONCLUSION: Clinically stable CF patients, who had comparable pulmonary function, exhibited increased REE% only in the presence of exocrine pancreatic insufficiency. REE% strongly correlated with BMI z-scores in pancreatic sufficiency. These findings support the hypothesis that pancreatic rather than pulmonary function may determine nutritional status as well as REE in CF.

Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis.

Acute recurrent/chronic pancreatitis (CP) is a complex multigenic disease. This is a case-control study consisting of 25 Greek patients with CP and a control population of 236 healthy Greek subjects. The whole coding area and neighboring intronic regions of the three genes were screened. Seventeen of 25 patients (68%) had mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: nine compound heterozygotes with either mild or severe mutations and eight heterozygotes. Four patients (16%) carried CFTR-modulating haplotypes V470-TG11-T5 and V470-TG12-T7. All were negative for PRSS1 gene mutations, while variants c.486C/T and c.738C/T were found in nine patients each, three homozygotes for the minor alleles. Two carried SPINK1 gene mutation p.N34S, one being transheterozygote with CFTR mutation p.F1052V. The promoter variant -253T>C was found in four individuals (one homozygous for the minor allele), all four being transheterozygotes with mutations in the CFTR gene as well. Finally two carried c.272C/T in the 3' untranslated region, one being a p.N34S carrier as well. In total, 80% (20/25) of patients had a molecular defect in one or both of the CFTR and SPINK1 genes, suggesting that mutations/variants in the CFTR plus or minus mutations in the SPINK1, but not the PRSS1 gene, may confer a high risk for recurrent pancreatitis.

Acquired von Willebrand's syndrome resulting from untreated hypothyroidism in two prepubertal girls.

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder associated with a number of different diseases, including hypothyroidism. We describe two prepubertal girls with AvWS and undiagnosed hypothyroidism due to thyroiditis Hashimoto. The patients had neither family history nor symptoms of bleeding disorders. Substitution therapy with levothyroxine led to normalization of the coagulation parameters. We report these cases in order to raise awareness among paediatricians so that the AvWS should be suspected and searched for with the appropriate laboratary tests in all cases of hypothyroidism. Moreover, patients with bleeding diathesis of unknown origin should also be investigated for hypothyroidism.

Cystic fibrosis and the pancreas: recent scientific advances.

Cystic fibrosis (CF) is inherited as an autosomal recessive trait due to a mutated gene carried on the long arm of chromosome 7. The protein coded by the CF gene (CFTR) is an apical chloride channel that regulates active chloride transport across epithelial cell membranes. The role of CFTR in pancreatic exocrine secretion is based on the concept that CFTR is localized to the apical membrane of the proximal duct epithelial cells. The primary ductal cell chloride channel abnormality results in dehydrated protein-rich secretions that obstruct the proximal ducts, leading to secondary acinar cell destruction, fibrosis, and exocrine pancreatic insufficiency in 85% of the CF population. A strong correlation between genotype and pancreatic phenotype is recognized. Advances in molecular biology such as cloning of lipase genes and gene therapy are challenging the field of pancreatic enzyme supplementation therapy.

Insulin improves clinical status of patients with cystic-fibrosis-related diabetes mellitus.

UNLABELLED: Cystic-fibrosis-related diabetes mellitus is frequently underdiagnosed and associated with deterioration of overall clinical status. The purpose of this prospective study was to investigate the influence of insulin on nutrition, lung function and clinical status of cystic fibrosis patients. For a period of 5 y, and at 6-mo intervals, body mass index, forced expiratory volume in 1 sec, Shwachman score, intravenous glucose tolerance test and first-phase insulin response were determined in 30 cystic fibrosis patients (age range 10-35 y) with exocrine pancreatic insufficiency. During the study period, six patients (3M and 3F; age range 15-22 y) developed diabetes and required insulin therapy. The decrease of first-phase insulin response coincided with deterioration of nutritional and clinical status, which improved significantly 6 mo after the institution of insulin. CONCLUSION: Insulin, as an anabolic hormone, could have an influence on body mass, which may affect pulmonary function and clinical condition in cystic fibrosis. It is important to identify cystic fibrosis individuals at risk of developing diabetes so that early insulin therapy is instituted.

Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease.

GOALS: To evaluate the efficacy of UDCA in arresting the progression of the early multifocal hepatic lesion to overt CF-related NBC. BACKGROUND: Focal biliary cirrhosis is an early hepatic pathologic change related to the ion transport defect in cystic fibrosis. The factors involved in the progression of focal to nodular biliary cirrhosis are not clear. Ursodeoxycholic--a hydrophilic, nontoxic, choleretic, and hepatoprotective exogenous bile acid--has been reported to be effective in the management of cholestatic liver disease. STUDY: For 10 years at 6-month intervals, 70 individuals with cystic fibrosis (38 men and 32 women; age range, 2--29 years) were examined using hepatosplenomegaly, liver function tests, and ultrasound liver scan. Patients demonstrating evidence of liver involvement at the onset or during the study received ursodeoxycholic acid 20 mg/kg body weight. RESULTS: After the administration of ursodeoxycholic acid, the progression of nodular biliary cirrhosis ultrasound changes was arrested, hepatic function was preserved, and no variceal bleeding was observed. No case of focal biliary cirrhosis progressed to nodular biliary cirrhosis. Furthermore, the multifocal, multilobular changes suggestive of focal biliary cirrhosis on ultrasound scan were reversed to normal. CONCLUSION: Ursodeoxycholic acid is effective in improving cholestasis and hepatic dysfunction in nodular biliary cirrhosis and, also, in reversing the early sonography findings suggestive of focal biliary cirrhosis. It is speculated that ursodeoxycholic acid may prove to affect the natural history of cystic fibrosis-related liver disease.

Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis.

Dysuria, uric acid crystalluria and hyperuricosuria developed in a child with cystic fibrosis and normal serum uric acid. Hyperuricosuria in this patient and two other children was directly related to ingestion of large amounts of pancreatic extract. In these three children, reducing pancreatic extract dosage by 85 percent lowered their purine intake by 307, 225, and 148 mg, respectively; urinary uric acid excretion decreased by 245, 239, and 158 mg. Overmedication resulted from parents' decisions to increase enzyme dosages. In our cystic fibrosis clinic, 15 of 32 patients screened at random were taking higher than the prescribed dose of pancreatic enzymes, and 14 of these 15 children were hyperuricosuric. On the basis of this information, we suggest that the minimal effective dose of pancreatic extract should be determined and adhered to for each child with cystic fibrosis to avoid potential renal injury from hyperuricosuria.

Diagnosis of exocrine pancreatic insufficiency in cystic fibrosis by the synthetic peptide N-benzoyl-L-tyrosyl-p-aminobenzoic acid.

The synthetic peptide N-benzoyl-L-tyrosyl-p-aminobenzoic acid is specifically cleaved by chymotrypsin to Bz-Ty and PABA. The liberated PABA is absorbed and excreted in the urine. Accordingly, PABA recovery reflects intraluminal chymotrypsin activity and is an index of exocrine pancreatic function. This test was evaluated in 24 patients with cystic fibrosis to determine its role in the diagnosis of exocrine pancreatic insufficiency. Cumulative percent PABA recovery in six hours was significantly lower in CF patients compared with the control group. No overlap was noted between the two groups. There was good correlation between PABA recovery, fecal chymotrypsin activity, and coefficient of fat absorption. These findings indicate that PABA recovery is significantly reduced in patients with CF and steatorrhea and may prove a practical and reliable test of pancreatic insufficiency.

Autoantibodies predicting diabetes mellitus type I in celiac disease.

UNLABELLED: Celiac disease (CD) and diabetes mellitus type I (DM-I) are both autoimmune diseases. Abnormal first-phase insulin response (FPIR) is associated with the prediabetic phase. Glutamic acid decarboxylase (GAD) and islet cell antibodies (ICAs) - especially the tyrosine phosphatase-like protein IA-2 antibodies - are considered to be serological markers of DM-I future development. The aim of this study is to investigate the presence of autoantibodies (GAD, IA-2) in individuals with CD, on a gluten-free diet, who have normal intestinal morphology. Thirty patients with CD (4-22, mean 15 years), 30 newly diagnosed diabetic children (2.5-16, mean 10 years) and 30 healthy subjects (7-35, mean 18 years) were investigated. Serum GAD and IA-2 autoantibodies were assessed by a quantitative enzyme-linked immunosorbent assay (ELISA) method in all patients and controls. Seven CD patients (23%), 28 diabetic children (93%) and none in the control group had positive GAD and IA-2 antibodies. The FPIR was normal in CD patients (>/=46 mU/l). CONCLUSIONS: GAD and IA-2 antibodies are detected in 23% of patients with CD. These patients may be at risk to develop DM-I. Regular follow-up and determination of FPIR for the early diagnosis of the prediabetic phase in patients with CD having circulating autoantibodies is recommended.

Role of electroretinography in the assessment of retinal function as an indicator of vitamin A status.

Hypovitaminosis A is associated with exocrine pancreatic insufficiency in cystic fibrosis. Peripheral retinal dysfunction is an early finding of vitamin A deficiency. We evaluated serum retinol and zinc as well as visual adaptation in 41 patients with cystic fibrosis, receiving generous pancreatic enzyme and micronutrient supplementation. Forty-one normal individuals matched for age and sex served as controls. Peripheral retinal function was measured by clinical electroretinography using an Electrophysiologic Personal Interfaced Computer and applying a standard protocol. Serum retinol in cystic fibrosis was significantly lower than that of the control group (0.30+/-0.01 versus 0.39+/-0.02 mg/l, p<0.001). Serum zinc concentrations were normal in the cystic fibrosis group (1.21+/-0.03 mg/l) and significantly higher than that of the control group (1.02+/-0.01 mg/l, p<0.001). The overall visual adaptation, however, was found to be normal and comparable in the two groups. It is concluded that, in cystic fibrosis, despite appropriate vitamin A supplementation, retinol serum concentration may be low. As serum retinol does not reflect vitamin A status, evaluation of visual adaptation may be a more appropriate way to monitor for vitamin A deficiency in cystic fibrosis.

Clinical application of immunological markers as monitoring tests in celiac disease.

The aim of this study was to investigate anti-gliadin (IgA-AGA and IgG-AGA), endomysial (IgA-EmA), and anti-reticulin (Ig-ARA) antibodies for monitoring celiac disease (CD) patients while on gluten-free and gluten-containing diets. Sera from 30 confirmed CD patients (13 boys, 17 girls), 1-24 years old, were examined for antibodies using ELISA (AGA) and Immunofluorescence (EmA, ARA) at 1, 3, 6, 9, and 12 months following institution of gluten-free diet and also at 3 and 6 months after challenge with gluten. One month following the exclusion of gluten from the diet, most antibodies are still positive. Twenty-three to 43% of antibodies remained positive by the end of the third month. At 6 and 9 months, 17% and 10% were positive, respectively. At 12 months no positive antibodies were detected. After gluten challenge, positive IgA-AGA and IgA-EmA titers were already demonstrated at 3 months (90% and 86%, respectively), while Ig-ARA titers showed a slow increase. Finally IgG-AGA responded with a slow decrease of titers to gluten-free diet levels and a fast increase upon provocation. The morphology of the intestine at diagnosis and during the periods of gluten-free diet and gluten challenge corresponds with the antibody titers. On the basis of these results, immunological markers may be applied to follow-up CD patients. IgA-AGA and IgA-EMA appear to be the most sensitive to dietary changes in gluten and correlate best with intestinal mucosal morphology.

Influence of jejunal morphology changes on exocrine pancreatic function in celiac disease.

BACKGROUND: Concurrent exocrine pancreatic dysfunction may be one of the factors implicated in malabsorption in untreated celiac disease, as shown by studies on bicarbonate and pancreatic enzyme secretion. The purpose of this study was to evaluate exocrine pancreatic function in relation to jejunal morphology in celiac disease. METHODS: Thirty-six patients fulfilling the ESPGHAN criteria for celiac disease, aged 3 to 18 years and 36 control subjects matched for age and sex were investigated. The design of the study included measurement of serum pancreatic isoamylase by a chromogenic method after selective inhibition of sialic isoamylase in the untreated phase in patients consuming a gluten-containing diet and after gluten elimination for a period of 1 year; fecal human elastase activity determined by enzyme-linked immunosorbent assay in patients consuming a gluten-free diet and again after gluten challenge for 6 months; correlation of serum pancreatic isoamylase and fecal elastase to the jejunal morphology, classified by criteria described by Marsch; the enzymes in the control group; and ultrasonography of the pancreas in both groups. RESULTS: Enzyme values obtained from celiac disease patients with normal mucosa were significantly higher than those obtained from patients with villous atrophy (p < 0.001) and comparable to those obtained from the control group. Serum pancreatic isoamylase activity increased to normal after gluten elimination, and human elastase activity decreased to values below 200 microg/g of stool after gluten challenge. Enzyme activity was related inversely to the degree of intestinal damage. The echogenicity of the pancreas was normal, regardless of enzyme activity or gut morphology. CONCLUSIONS: Exocrine pancreatic function is abnormal in celiac disease when mucosal atrophy is present. Exocrine pancreatic function parameters are associated with the changes of intestinal mucosal morphology in three consecutive phases of the disease.