Maria Fotoulaki

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.

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

BackgroundA 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. MethodsOne 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. ResultsAt 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. ConclusionsThe 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.

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.

Clinical Application of Immunological Markers as Monitoring Tests in Celiac Disease

The aim of this study was to investigateanti-gliadin (IgA-AGA and IgG-AGA), endomysial(IgA-EmA), and anti-reticulin (Ig-ARA) antibodies formonitoring celiac disease (CD) patients while ongluten-free and gluten-containing diets. Sera from 30confirmed CD patients (13 boys, 17 girls), 1-24 yearsold, were examined for antibodies using ELISA (AGA) andImmunofluorescence (EmA, ARA) at 1, 3, 6, 9, and 12 months following institution of gluten-freediet and also at 3 and 6 months after challenge withgluten. One month following the exclusion of gluten fromthe diet, most antibodies are still positive.Twenty-three to 43% of antibodies remained positive by theend of the third month. At 6 and 9 months, 17% and 10%were positive, respectively. At 12 months no positiveantibodies were detected. After gluten challenge, positive IgA-AGA and IgA-EmA titers werealready demonstrated at 3 months (90% and 86%,respectively), while Ig-ARA titers showed a slowincrease. Finally IgG-AGA responded with a slow decreaseof titers to gluten-free diet levels and a fast increaseupon provocation. The morphology of the intestine atdiagnosis and during the periods of gluten-free diet andgluten challenge corresponds with the antibody titers. On the basis of these results,immunological markers may be applied to follow-up CDpatients. IgA-AGA and IgA-EMA appear to be the mostsensitive to dietary changes in gluten and correlatebest with intestinal mucosal morphology.

Prevalence of malnutrition and obesity among cystic fibrosis patients

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.

The Impact of Pulmonary Arterial Pressure on Exercise Capacity in Mild-to-Moderate Cystic Fibrosis: A Case Control Study

Background. Pulmonary hypertension (PH) is an often complication of severe cystic fibrosis (CF); however, data on the presence and impact of pulmonary vasculopathy in adult CF patients with milder disease, is very limited. Aim. To investigate, for the first time, the impact of systolic pulmonary arterial pressure (PASP) on maximal exercise capacity in adults with mild-to-moderate cystic fibrosis, without PH at rest. Methods. This is a Case Control study. Seventeen adults with mild-to-moderate CF, without PH at rest (cases) and 10 healthy, nonsmoking, age, and height matched controls were studied. All subjects underwent maximal cardiopulmonary exercise testing and echocardiography before and within 1 minute after stopping exercise. Results. Exercise ventilation parameters were similar in the two groups; however, cases, compared to controls, had higher postexercise PASP and decreased exercise capacity, established with lower peak work rate, peak O2 uptake, anaerobic threshold, and peak O2 pulse. Furthermore, the change in PASP values before and after exercise was strongly correlated to the parameters of exercise capacity among cases but not among controls. Conclusions. CF adults with mild-to-moderate disease should be screened for the presence of pulmonary vasculopathy, since the elevation of PASP during exercise might contribute to impaired exercise capacity.

Primary Intestinal Lymphangiectasia: Is It Always Bad? Two Cases with Different Outcome

Primary intestinal lymphangiectasia (PIL) or Waldmanns disease is a rare protein-losing gastroenteropathy of unknown etiology. Less than 200 cases have been reported globally. Patients may be asymptomatic or present edema, lymphedema, diarrhea, ascites and other manifestations. We report two pediatric cases with PIL with extremely different outcome in a 3-year follow-up period. The first patient presented with persistent diarrhea, hypoalbuminemia and failure to thrive, while the second patient presented with an abrupt eyelid edema. Hypoproteinemia was the common laboratory finding for the two patients and upper gastrointestinal endoscopy established the diagnosis. The first patient relapsed five times during the follow-up period after the diagnosis had been made and required intravenous albumin administration and micronutrient supplementation. The second patient revealed normal gastrointestinal endoscopy 4 months after the diagnosis had been established; he followed an unrestricted diet and remained asymptomatic throughout the follow-up period. PIL can be either severe, affecting the entire small bowel, leading to lifetime disease, or sometimes affects part of the small bowel, leading to transient disorder.

Cystic fibrosis genetic counseling difficulties due to the identification of novel mutations in the CFTR gene

BACKGROUND The Cystic Fibrosis database includes amongst the 1893 gene mutations and polymorphisms a lot of missense mutations, the disease status of which still remains unproven. In populations with high rates of CFTR mutation heterogeneity, molecular diagnosis is difficult often causing counseling difficulties especially in cases of rare and/or novel mutations. METHODS Approaches to counseling in cases of novel variants. RESULTS Thirty-seven novel variants (4 synonymous, 24 missense, 2 frameshift and 10 intronic substitutions) were identified and evaluated with the help of in silico tools. CONCLUSIONS In a diagnostic environment the answers have to be given within a specific timeframe, the in silico tools in combination with the phenotype offer some help but their diagnostic value is limited and cannot be used in isolation for the determination of the severity of the mutation.

Plasma citrulline levels in paediatric patients with celiac disease and the effect of a gluten-free diet.

Objective Citrulline is a nonprotein amino acid synthesized in the small intestine. The aim of this study isto explore plasma citrulline levels in children with celiac disease (CD) and monitor the time-related changes of these levels after initiation of a gluten-free diet (GFD). Methods Fasting-plasma citrulline levels were determined by high-performance liquid chromatography in (i) 23 patients with CD before the institution of GFD, (ii) 20 patients with CD under treatment for more than 2 years responsive to a GFD, (iii) 10 children with gastrointestinal symptoms and normal small bowel biopsy, and (iv) 20 healthy controls. In group A, citrulline levels were also measured after 1, 3, 6, and 12 months on a GFD. Results Mean plasma citrulline levels were lower in untreated patients with CD (24.5±4.9) than in patients onaGFD (31.2±6.7 &mgr;mol/l, P<0.001), patients with gastrointestinal symptoms and normal intestinal mucosa (30.3±4.7 &mgr;mol/l, P<0.01), and healthy controls (32.4±7.5 &mgr;mol/l, P<0.001). In untreated patients with CD,an inverse correlation was observed between citrulline concentrations and the severity of villous atrophy (r=−0.67, P<0.01). After 1 month on a GFD, patients hadsignificantly higher levels than before diet (P<0.05) and after 3 months on diet, levels were similar to those observed in the healthy controls. Conclusions Plasma citrulline levels are lower in celiacs reflecting small bowel involvement in this disease. After ashort period on GFD, citrulline levels increased rapidly, indicating that citrulline is a sensitive marker of the positiveeffect of GFD on intestinal repair.

International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: Associated factors and outcome

BACKGROUND Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. METHODS A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. RESULTS 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p=0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p=0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p<0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p=0.03), liver disease (22% vs. 12%, p=0.004), diabetes mellitus (49% vs. 25%, p=0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p=0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p=0.04), constipation with incomplete episodes (39% vs. 11%, p=0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p=0.02). CONCLUSION DIOS is a multifactorial condition having a similar incidence in children and adults. We show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis.