F. Ferretti

Coeliac disease in Williams syndrome

BACKGROUND Coeliac disease (CD) has been reported in several patients affected by chromosomal disorders, including Down syndrome (DS) and Turner syndrome (TS). CD has also been found in sporadic Williams syndrome (WS) patients. In this study, CD was evaluated in a consecutive series of patients with WS, in order to estimate if the prevalence of CD in WS patients is higher than in the general population. METHODS AND RESULTS A consecutive series of 63 Italian patients with WS was studied by analysing the dosage of antigliadin antibodies (AGA) IgA and antiendomisium antibodies (AEA). In patients with positive AGA and AEA, small bowel biopsy was performed. The prevalence of CD in our WS population was compared with that estimated in a published series of 17 201 Italian students. Seven WS patients were found to be positive for AGA IgA and AEA. Six of them underwent small bowel biopsy, which invariably disclosed villous atrophy consistent with CD. The prevalence of CD in the present series of WS patients was 9.5% (6/63), compared to 0.54% (1/184) in the Italian students (p<0.001). CONCLUSION The present results suggest that the prevalence of CD in WS is higher than in the general population and is comparable to that reported in DS and TS. AGA and AEA screening is recommended in patients with WS.

DOWN'S SYNDROME AND CELIAC DISEASE: THE PREVALENCE OF HIGH IGA-ANTIGLIADIN ANTIBODIES AND HLA-DR AND DQ ANTIGENS IN TRISOMY 21

Patients with Downs syndrome (DS) or celiac disease (CD) have altered immune systems. Autoimmune diseases have been described in both conditions; the coexistence of DS and CD has been occasionally reported, but a clear relationship has not been definitely established. In this study we determined IgA antigliadin antibodies (IgA-AGA) in 155 children with DS, and the results were compared with those of the control groups formed by 320 children affected by upper-respiratory tract infections and 115 children with gastrointestinal symptoms but with normal jejunal mucosa. High IgA-AGA levels were found in 26% of DS patients, in 1% of the first control group and in 10% of the second control group. Such differences are statistically significant. Twenty-one DS patients with high IgA-AGA levels and gastrointestinal symptoms underwent jejunal biopsy, and total villous atrophy was found in seven of them (33.33%). HLA-DR and -DQ antigens were also determined in 75 DS patients (20 with high and 55 with normal IgA-AGA levels), and the percentages of the different phenotypes were compared in the two groups and with those of a control group. No statistically significant difference was found, but DR3, DR7, and DQ2 alleles were always present in DS patients with jejunal atrophy. Our study confirms the data reported in the literature about higher levels of IgA-AGA in DS patients and the relatively high incidence of CD in this group of patients.

Irreversible Intestinal Failure : Prevalence and Prognostic Factors

Background and Aim: Parenteral nutrition (PN) is the primary treatment for intestinal failure, which is considered irreversible in patients who remain partially or fully dependent on PN. Causes of irreversible intestinal failure are short bowel syndrome (SBS), motility disorders (MD), and severe protracted diarrhea (SPD). The aim of this study was to report the clinical outcome in these patients in relation to the underlying disease. Patients and Methods: From January 1, 1989 to December 31, 2006, 218 intestinal failure patients were observed in our center, but only 96 (48 SBS, 39 SPD, and 9 MD) were included because they required at least 50% of their total calories as PN for not less than 3 months. In these patients, survival and complication rates were evaluated. Results: The survival rate was significantly higher in SBS patients than in the other groups (P < 0.01). SBS patients showed a higher rate of major complications, although only intestinal failure–associated liver disease was significantly higher (P < 0.001). In our series, MD was the main cause of irreversible intestinal failure. Conclusions: The potential for bowel adaptation is higher in surgical than in medical causes of intestinal failure and does not seem to be influenced by complications of intestinal failure. SBS, although worsened by the major number of complications, was not the main category contributing to intestinal failure.

Clinical Value of Immunoglobulin A Antitransglutaminase Assay in the Diagnosis of Celiac Disease

OBJECTIVES. Our goal was to evaluate the possible correspondence between antitissue transglutaminase of immunoglobulin A class levels and stage of mucosal damage in patients affected by celiac disease. In addition, we assessed clinical use of antitissue transglutaminase values to predict biopsy results. METHODS. One thousand eight hundred eighty-six consecutive patients with symptoms suggestive of celiac disease and 305 healthy controls underwent determination of serum levels of immunoglobulin A and antitissue transglutaminase. An intestinal biopsy was performed in subjects with antitissue transglutaminase levels ≥4 IU/mL and in subjects with negative antitissue transglutaminase levels but with clinical suspicion of celiac disease. Histologic grading of celiac disease was consistent with the Marsh classification. RESULTS. One hundred eighty-six subjects with positive antitissue transglutaminase levels and 91 patients with negative antitissue transglutaminase levels were submitted to biopsy. In all healthy subjects, antitissue transglutaminase results were negative. Histologic evaluations in patients with positive antitissue transglutaminase levels gave the following results: type 0 in 25 patients, type 1 in 3 patients, type 2 in 4 patients, type 3a in 22 patients, type 3b in 74 patients, and type 3c in 58 patients. None of the patients with negative antitissue transglutaminase levels showed histologic findings suggestive of celiac disease. The mean antitissue transglutaminase values in patients without mucosal atrophy were significantly lower than in patients with mucosal atrophy. Antitissue transglutaminase values ≥20 IU/mL were found in only 1 patient without mucosal atrophy. CONCLUSIONS. Our study found a strong correspondence between antitissue transglutaminase levels and stage of mucosal injury; antitissue transglutaminase values >20 IU/mL seemed to be strongly predictive of mucosal atrophy.

Screening for celiac disease in patients with deletion 22q11.2 (DiGeorge/velo-cardio-facial syndrome).

The DiGeorge/velo-cardio-facial syndrome (DG/ VCFS) is characterized by minor facial anomalies, conotruncal heart defect, palatal anomalies, immunological deficit, and neonatal hypocalcemia [Lipson et al., 1991; Wilson et al., 1993; Ryan et al., 1997]. Most of the cases of DG/VCFS are due to a microdeletion of chromosome 22q11.2 (del22q11.2) [Scambler et al., 1991; Driscoll et al., 1993]. This chromosomal anomaly is considered to be among the most frequent causes of genetic syndromes with an estimated incidence of 1/4,000 livebirths [Devriendt et al., 1998]. Gastrointestinal symptoms occur in patients with DG/VCFS in the first years of life [Goldberg et al., 1993; Ryan et al., 1997; Piccoli, 2000]. Particularly, feeding difficulties are considered to be due to dysmotility of the pharyngoesophageal area, which is derived from the third and fourth pharyngeal arches involved in the pathogenesis of the syndrome [McDonald-McGinn et al., 1999; Rommel et al., 1999; Vantrappen et al., 1999]. Feeding problems seem to be the prevalent cause of underweight in the first years of age of DG/VCFS patients; weight growth improves when feeding difficulties become uncommon [Digilio et al., 2001]. To our knowledge, celiac disease (CD) has never been reported in patients with DG/VCFS. But, several other chromosomal syndromes are frequently associated with CD. In fact, screening for CD has been recommended in patients with Down syndrome [Castro et al., 1993; George et al., 1996], Turner syndrome [Bonamico et al., 1998; Ivarsson et al., 1999], and Williams syndrome [Giannotti et al., 2001], since the prevalence of CD in these conditions ranges between 4.5 and 10.5%. The analysis of clinical symptoms has shown an atypical or silent CD in subjects with these syndromes, and the screening tests for CD are considered to be of primary importance in identifying patients who should undergo jejunal biopsy. Considering the high prevalence of CD in these chromosomal abnormalities, we carried out a screening for CD in patients with DG/VCFS, to determine if del22q11.2 could be another condition at risk for CD. Autoimmune disorders, including juvenile rheumatoid arthritis [Rasmussen et al., 1996; Sullivan et al., 1997; Verloes et al., 1998], Graves disease [Pong et al., 1985], and hemolytic anemia [Sherry et al., 1990] have been reported in patients with del22q11.2. Thus, it is possible that other autoimmune disorders are present with increased frequency in patients with del22q11.2. From January 1997 to June 2001, 48 children with DG/VCFS above the age of 18 months underwent a screening forCD in the setting of a follow-upprogram for the syndrome.Therewere28boysand20girls. Their age at time of the screening ranged from 1.8 to 15.5 years (mean SD 5.89 3.84 years). Most patients (43/481⁄4 90%) were more than the age of 3 years. All patients had typical clinical characteristics of the syndrome. The clinical diagnosis of DG/VCFS was confirmed by Fluorescent in situ hybridization (FISH) with Sc11.1 and Co23 probes [Dallapiccola et al., 1996] demonstrating the del22q11.2. All patients were receiving a gluten-containing diet. Anamnestic informations about signs and symptoms in relation to a malabsorption condition were investigated by interview. In particular, the presence of chronic diarrhea, feeding difficulties, and abdominal pain were studied. Weight and height parameters at the time of the screening were recorded and plotted on standard percentile growth charts by Tanner et al. [1966]. Serum immunoglobulins IgA were measured. Antigliadin antibodies (AGA) IgA were studied by enzyme immunoassay (Pharmacia Diagnostic AB, Uppsala, Sweden). A test was considered positive if the sample result was >35 AU. Antiendomysium antibodies (AEA) IgA were determined by indirect immunofluorescence on a section of the lower third of oesophagus of the monkey. The dilution of serum was 1:5. Sera showing fluorescence in the endomysial lining of smooth muscle fibers at 1/5 or higher were considered positive. In presence of positivity of AEA IgA, small-bowel biopsy with Watson’s capsule or during endoscopy was performed. The diagnosis of CD was made when villous atrophy with hyperplasia of the crypts and increased *Correspondence to: Dr. Maria Cristina Digilio, Medical Genetics, Bambino Gesu Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy. E-mail: digilio@opbg.net

Thyroid autoimmunity in children with coeliac disease: a prospective survey.

Background Thyroid autoimmunity (TA) is often associated with coeliac disease (CD). Objective To evaluate, in children and adolescents with CD on a gluten-free diet (GFD): (1) the prevalence of TA; (2) the impact of TA on growth and the need for L-thyroxine (L-T4) treatment, during a longitudinal survey. Method Between January and December 2005, 545 patients with CD, prospectively followed up until December 2007, and 622 controls were screened for TA. Antithyroperoxidase and antithyroglobulin antibodies were assayed and, if positive, serum free tri-iodothyronine, free thyroxine and thyroid-stimulating hormone (TSH) assays and thyroid ultrasound were performed. L-T4 was started if TSH was >5.5 mU/ml at two successive measurements. Results There was no significant difference in TA prevalence between patients with CD on a GFD (10%) and controls (8.2%). Duration of GFD differed significantly in coeliac patients with TA in comparison with those without TA (7.9±0.9 and 10.2±0.3 years, p<0.001), but no significant difference was found for weight and height gain (1.8±1.0 vs 3.7±1.5 and 2.1±1.2 kg/year vs 4.0±1.1 cm/year, respectively). At the end of the follow-up an increase of 7% in the prevalence of patients with CD with TA requiring L-T4 was found. Conclusions TA seems no more common in paediatric and adolescent patients with CD on a GFD than in controls; its clinical evolution does not seem to impact on growth. Therefore, a long-term regular screening programme for thyroid disease may not be necessary for all patients with CD on a GFD, but only for those who are suspected of having thyroid diseases.

Intestinal adaptation in short bowel syndrome

Abstract Short bowel syndrome (SBS) either in adults or in children is considered as an indication of small bowel transplantation (SBT).1,2 Severity and prognosis depend on various factors such as small bowel resection length, patients age, and intestinal length at the time of resection. In pediatrics, most patients, affected by SBS undergo resection when neonates or anyway in the first months of life (necrotizing enterocolitis, congenital anomalies of gastrointestinal troct, abdominal wall defects); only in few patients pathology begins later on, usually for tumoral, vascular or Crohns diseases. Intestinal adaptation process, characterized by epithelial hyperplasia, has an early onset, within the first days after resection, with a progressive increase of intestinal absorptive surface; such adapting capacity is greater for ileum rather than for jejunum.2–5 This intestinal adaptation process with mucosal hyperplasia requires an enteral nutrition which acts both directly by nutrients contact on intestinal epithelium and by stimulating the secretion of trophic factors such as enteroglucagon, epidermal growth factor and insulin-like growth factor-1. From the clinical point of view, the term “adaptation” means the total nutritional autonomy with a satisfying height and weight growth. In patients who initially need parenteral nutrition (PN), total intestinal adaptation is considered as attained when they can stop PN. The aim of the present study is to evaluate retrospectively our series of severe SBS patients, with residual intestine shorter than 100 cm, who consequently required a prolonged PN, verifying the possibility and the time of intestinal adaptation and therefore the existence or not of an indication to intestinal transplantation.

Beverage consumption and paediatric NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, due to the increased worldwide incidence of obesity among children. It is now clear enough that of diet high in carbohydrates and simple sugars are associated with hepatic steatosis and non-alcoholic steatohepatitis (NASH). Several studies have shown that an increased consumption of simple sugars is also positively associated with overweight and obesity, and related co-morbidities, such as type 2 diabetes, metabolic syndrome and NAFLD. It is difficult to define the role of the various components of soft drinks and energy drinks in the pathogenesis of NAFLD and its progression in NASH, but the major role is played by high calorie and high sugar consumption, mainly fructose. In addition, other components of these beverages (e.g. xanthine) seem to have an important role in the pathogenesis of metabolic disorders, crucial pathways involved in NAFLD/NASH. The drastic reduction in the consumption of energy drinks and soft drinks is an appropriate intervention for the prevention of obesity and NAFLD in young people.

Is the screening for celiac disease useful in anorexia nervosa

The main objective of the study was to prospectively assess if the prevalence of celiac disease (CD) in patients with anorexia nervosa (AN) is higher than that reported in the general population to require a regular screening program. The study was conducted at the Neuropsychiatry Unit of “Bambino Gesù” Children’s Hospital in Rome from January 2005 to December 2010. All patients with diagnosis of AN according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria were screened for CD. One hundred and seventy-seven patients (33 males and 144 females) were enrolled. Only one patient was found to be affected with CD as confirmed by intestinal biopsy. The overall prevalence of CD in AN patients was 0.6 % which is similar to that observed in the general population. In conclusion, AN patients do not seem to require a regular screening program for CD. The screening for CD may be useful in selected AN patients in which the symptoms are only partially responding to psychiatric interventions.

Association between celiac disease and primary lactase deficiency.

Primary lactase deficiency (PLD) is a common inherited condition caused by a reduced activity of lactase. Two single-nucleotide polymorphisms C/T-13910 and G/A-22018 upstream of the lactase gene are associated with lactase nonpersistence. In celiac disease (CD) patients, lactose intolerance could be due to secondary lactase deficiency and to PLD. The aim of this study were to evaluate the association of PLD and CD using genetic test, and to define the prevalence of PLD in celiac subjects compared with a control population. A total of 188 controls and 92 biopsy-proven CD patients were included in the study. More than 70% of all subjects were found homozygous for the polymorphisms. Differences in the prevalence of PLD were not found between CD patients and controls.In conclusions, the hereditary lactase deficiency is frequent in Italian CD children as in control population.