Genetics of Vesicoureteral Reflux.

Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder to the upper urinary tract. It is the most common congenital urological anomaly affecting 1-2% of children and 30-40% of patients with urinary tract infections. VUR is a major risk factor for pyelonephritic scarring and chronic renal failure in children. It is the result of a shortened intravesical ureter with an enlarged or malpositioned ureteric orifice. An ectopic embryonal ureteric budding development is implicated in the pathogenesis of VUR, which is a complex genetic developmental disorder. Many genes are involved in the ureteric budding formation and subsequently in the urinary tract and kidney development. Previous studies demonstrate an heterogeneous genetic pattern of VUR. In fact no single major locus or gene for primary VUR has been identified. It is likely that different forms of VUR with different genetic determinantes are present. Moreover genetic studies of syndromes with associated VUR have revealed several possible candidate genes involved in the pathogenesis of VUR and related urinary tract malformations. Mutations in genes essential for urinary tract morphogenesis are linked to numerous congenital syndromes, and in most of those VUR is a feature. The Authors provide an overview of the developmental processes leading to the VUR. The different genes and signaling pathways controlling the embryonal urinary tract development are analyzed. A better understanding of VUR genetic bases could improve the management of this condition in children.

Coeliac disease: a potentially treatable health problem of Saharawi refugee children.

OBJECTIVE: To characterize the clinical and nutritional impact of coeliac disease (gluten-sensitive enteropathy) among Saharawi children living as refugees in Algeria. METHODS: A total of 65 Saharawi children with coeliac disease were compared with 71 age-matched non-coeliac controls. For each participant, the clinical history was taken and a clinical examination, non-quantitative 24-hour dietary recall, anthropometric and skinfold measurements, bioelectric impedance analysis (BIA) of body composition, and venous blood sampling for haemoglobin determination were performed. RESULTS: Gluten-containing food, especially bread, was the staple diet of Saharawi children. Abdominal pain and distension were significantly commoner among children with coeliac disease than in controls (P < 0.05). The mean height-for-age was significantly lower in such children than in controls (-2.5 +/- 1.4 units vs -1.8 +/- 1.3 units, respectively, P < 0.01). No significant differences were found for either skinfold or BIA measurements. Haemoglobin values tended to be lower in children with coeliac disease than in controls. CONCLUSIONS: Coeliac disease has a negative effect on the health status of Saharawi refugee children. Because of the high prevalence of the condition in the Saharawi, a specific programme for treating all affected individuals should be established. Further studies are required to quantify the impact of coeliac disease in other areas of the developing world.

The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence.

Celiac disease (CD) is a multifactorial disorder of the small intestine caused by a permanent dietary intolerance to gluten. The combined presence of the HLA class II DQA1*0501 and DQB1*0201 alleles represents the major genetic component for disease predisposition. It has been shown that the Saharawi refugees living in northern Africa have a very high frequency of CD. In the present study we analysed this population to evaluate the degree of association with CD of the haplotypes and genotypes at the main HLA-DQB1 and DQA1 disease loci. We found a strong association of the DR3, DQB1*0201-DQA1*0501-positive haplotypes and genotypes. A very high frequency of DR3, DQB1*0201-DQA1*0501 was also observed in the general Saharawi population. These results indicate that there is a good correlation between disease prevalence and frequency of the main predisposing haplotype in the background population. However, the correlation is incomplete because similar frequencies of DR3 are also observed in populations such as the Sardinians showing a much lower prevalence of CD. We can conclude that the distribution of DQ genes in the Saharawi population only provides a partial explanation for the high prevalence of CD. Other factors, such as rapidly changing dietary habits and/or non-DQ genes, may also play some role.

Compliance with gluten-free diet in adolescents with screening-detected celiac disease: a 5-year follow-up study.

After 5 years of treatment, 22 patients with celiac disease, diagnosed by means of serologic mass screening (mean age, 17.9 years), showed a lower compliance with a gluten-free diet and frequent positivity of serum anti-endomysium antibodies (32%) in comparison with a group of 22 age-matched patients diagnosed because of "typical" symptoms during childhood.

Why is coeliac disease endemic in the people of the Sahara?

The prevalence of antiendomysial antibody (AEA) in 989 Saharawi children was 5.6%. Intestinal biopsies in a subsample confirmed that AEA is a marker of coellac disease in people living in a developing country.

Is the sugar intestinal permeability test a reliable investigation for coeliac disease screening?

BACKGROUND: The lactulose/mannitol (L/M) intestinal permeability test is a simple, non-invasive screening test for coeliac disease. The reliability of the L/M test has so far only been tested in selected groups of patients with coeliac disease. AIM: To evaluate the reliability of the L/M test in a group of patients with coeliac disease who had been diagnosed during mass serological screening of the general population. PATIENTS AND METHODS: Twenty nine patients with coeliac disease detected by screening and 54 age matched coeliac disease free controls aged 11-15 years underwent an L/M test with 5 g lactulose and 2 g mannitol in isotonic aqueous solution. Urinary sugars were measured by high performance liquid chromatography. RESULTS: The median % urinary recovery of lactulose (lactulose UR) was significantly higher in patients with coeliac disease than in controls (0.63 v 0.18, p < 0.001). The mean mannitol % UR was lower in patients with coeliac disease than in controls (17.6 v 18.5) but the difference was not significant. The median urinary L%/M% ratio was significantly higher in patients with coeliac disease than in controls (0.038 v 0.014, p < 0.001). However, 16 of the 29 patients with coeliac disease showed an L%/M% ratio within normal limits (< 0.044). CONCLUSIONS: The L/M intestinal permeability test is not a valuable tool for screening of coeliac disease in the general population. The pattern of the urinary probe recovery suggests that many patients with coeliac disease could remain symptomless because the extent of their intestinal mucosal damage is small ("short" coeliac disease).

The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects.

BACKGROUND: Recent studies suggest that coeliac disease (CD) is one of the commonest, life-long disorders in Italy. The aims of this multicentre work were: (a) to establish the prevalence of CD on a nationwide basis; and (b) to characterize the CD clinical spectrum in Italy. PATIENTS AND METHODS: Fifteen centres screened 17,201 students aged 6-15 years (68.6% of the eligible population) by the combined determination of serum IgG- and IgA-antigliadin antibody (AGA) test; 1289 (7.5%) were IgG and/or IgA-AGA positive and were recalled for the second-level investigation; 111 of them met the criteria for the intestinal biopsy: IgA-AGA positivity and/or AEA positivity or IgG-AGA positivity plus serum IgA deficiency. RESULTS: Intestinal biopsy was performed on 98 of the 111 subjects. CD was diagnosed in 82 subjects (75 biopsy proven, 7 not biopsied but with associated AGA and AEA positivity). Most of the screening-detected coeliac patients showed low-grade intensity illness often associated with decreased psychophysical well-being. There were two AEA negative cases with associated CD and IgA deficiency. The prevalence of undiagnosed CD was 4.77 x 1000 (95% CI 3.79-5.91), 1 in 210 subjects. The overall prevalence of CD, including known CD cases, was 5.44 x 1000 (95% CI 4.57-6.44), 1 in 184 subjects. The ratio of known to undiagnosed CD cases was 1 in 7. CONCLUSIONS: These findings confirm that, in Italy, CD is one of the most common chronic disorders showing a wide and heterogeneous clinical spectrum. Most CD cases remain undiagnosed unless actively searched.

Dietary compliance in screening-detected coeliac disease adolescents.

In 1992-94 we screened 6315 students for coeliac disease (CD) by testing antigliadin antibodies (AGA) as the first-level investigation. We found 28 biopsy-proven coeliac patients who were invited to start the gluten-free diet (GFD). The aim of this study was a clinical and laboratory follow-up in these screening-detected coeliac adolescents. Patients were 17 females and 11 males with a mean age at diagnosis of 12.8 +/- 1 years (range 11-4). Mean follow-up duration time was 23 +/- 7 months (range 9-37). Twenty-three of the 28 screening-detected coeliac patients came to the control visit, 3 refused the follow-up and 2 subjects were not found. Twelve patients (52.2%) stated that they never ate any gluten-containing food, while 11 of them (47.8%) reported occasional transgressions to the diet. GFD acceptance was reported as good (n = 6), moderate (n = 11) or low (n = 6). After starting the GFD, signs of improvement were seen in most patients, such as weight gain, increased height velocity and increased feeling of well-being. AGA (both IgG and IgA classes) and antiendomysium antibodies (AEA) were normal in 19 subjects, 2 cases had IgG-AGA and AEA positivity, 1 patient showed abnormal AGA and AEA levels, while isolated IgA-AGA positivity persisted in 1 case. This study shows that even silent CD cases can clinically benefit from the GFD. The consequences of occasional transgressions to the GFD remain unclear.

High prevalence of undiagnosed coeliac disease in 5280 Italian students screened by antigliadin antibodies.

Many cases of coeliac disease are currently undiagnosed. We carried out a pilot study on screening for coeliac disease in a school population. The screening protocol consisted of three parts: (1) IgG and IgA antigliadin antibody (AGA) assay; (2) antiendomysium antibody and total serum IgA determinations; (3) jejunal biopsy. A total of 5280 students aged 11-15 years (71.7% of the eligible population) underwent the first evaluation; 113 subjects performed the second tests and 35 of these needed the third investigation. Coeliac disease was diagnosed in 23 cases, most of which were atypical or silent forms. The prevalence of undiagnosed coeliac disease was 4.36 per 1000 screened subjects (95% CI 2.58-6.14) and 5.03 per 1000 (95% CI 3.41-6.65) in the general population. The ratio of known to undiagnosed cases was 1 to 6.4. This high prevalence of undiagnosed coeliac disease raises a number of problems that require further evaluation.

Coeliac disease in the year 2000: exploring the iceberg.

It is now generally believed that subclinical coeliac disease is common in the general population. We have undertaken screening for this disorder in a school district in central Italy. Screening was divided into three levels: first, IgG and IgA antigliadin antibody (AGA) assay on capillary blood obtained by finger prick; second, AGA plus IgA anti-endomysium antibody (AEA) test and measurement of serum immunoglobulins in venous blood; and third, intestinal biopsy. 3351 students (66% of the eligible population) aged 11-15 years attended first-level screening. 71 (2%) were recalled because of AGA positivity; 18 of these satisfied second-level criteria and underwent intestinal biopsy. Coeliac disease was diagnosed in 11 subjects, most of whom had no serious symptoms. Selective IgA deficiency was found in 4 subjects, 1 of whom also had coeliac disease. The prevalence of subclinical coeliac disease in the study group was 3.28 per 1000. Coeliac disease screening is feasible and involves only slight discomfort to the general population. Such screening can detect large numbers of cases of coeliac disease, which can be treated with a gluten-free diet. Many subclinical cases of coeliac disease would not be detected by screening only a selected group of at-risk patients.

Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study.

This study aimed to investigate the effects of chronic ingestion of small amounts of gliadin on children with coeliac disease. A four week challenge was performed on 20 children who had been on a gluten free diet for mean (SD) 14 (3) months. They were given a daily dose of either 100 mg (group A, n = 10, mean age 4 (2) years) or 500 mg of gliadin (group B, mean age 5 (3) years). The effects of the gliadin were monitored by morphometric study of the jejunal mucosa, intestinal permeability test with cellobiose/mannitol, and serum antigliadin antibody test. After the challenge, group A patients showed a significant increase in the mean intraepithelial lymphocyte count (before challenge 11 (3), afterwards 19 (6)) and a decrease in the villous height/crypt depth ratio (beforehand 1.5 (0.1), afterwards 1.3 (0.2)), while the intestinal permeability test remained normal and the IgA-antigliadin antibody increased in four of 10 children. After the challenge group B showed more pronounced histological changes, an increase in the mean urinary cellobiose/mannitol % (beforehand 0.028 (0.020), afterwards 0.058 (0.028)), and IgA-antigliadin antibody positivity in six of eight subjects. The discriminant analysis function showed that the pretreatment group, group A after challenge, and group B after challenge were correctly classified in 90% of cases by functions based on the individual intraepithelial lymphocyte count and the villous height/crypt depth ratio. This study shows that chronic ingestion of small amounts of gluten causes dose-dependent damage to the small intestinal mucosa in children with coeliac disease. The predictive value of laboratory tests, such as the antigliadin antibody test and the intestinal permeability test seems to be lower in treated patients than in those with active coeliac disease.

Energy and nutrient intake of patients with mild-to-moderate chronic renal failure compared with healthy children: an Italian multicentre study.

Nutritional counselling is important in the management of children with chronic renal failure (CRF). In 1988, a controlled European multicentre study was started to evaluate the effects of a low-protein diet on the progression of CRF in children. To assess the energy, macro- and micronutrient intake, 4-day weighed dietary records were obtained from 50 children with low to moderate CRF (creatinine clearance 65 to 15 ml/min per 1.73 m2) and from 93 healthy children. The mean energy intake was 90%-93% of the recommended dietary allowance for Italian children in controls and 76%-88% in CRF patients. The mean protein intake was 2.1-3.1 g/kg per day in controls and 1.6-2.7 g/kg per day in CRF patients. Overall, the energy intake was 10% and the protein intake 33% lower in CRF patients than in healthy children. Children with CRF consumed less cholesterol, calcium and phosphorus than healthy children. The lower spontaneous intake of energy, protein and other nutrients should be taken into account when planning the nutrition of children with CRF.

Documented latent coeliac disease in a child with insulin-dependent diabetes mellitus.

The histological development of coeliac disease has been documented in a child with insulin-dependent diabetes mellitus (IDDM). Serum antigliadin IgG was temporarily present at the onset of IDDM. It is assumed that IDDM may exert a trigger effect on the development of coeliac disease.