Antonio Carroccio

Intolerance of Cow's Milk and Chronic Constipation in Children

Background: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cows milk among children. On the basis of a prior open study, we hypothesized that intolerance of cows milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. Methods: We performed a double-blind, crossover study comparing cows milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythoma or edema. After 15 days of observation, the patients received cows milk or soy milk for 2 weeks. After a one week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. Results: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cows milk had a response. In all 44 children with a response, the response was confirmed with a double blind challenge with cows milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P = 0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P < 0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P = 0.008), and signs of hypersensitivity, such as specific IgE antibodies to cows-milk antigens (31 of 44 vs. 4 of 21, p < 0.001). Conclusions: In young children, chronic constipation can be a manifestation of intolerance of cows milk.

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders

Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.

Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity.

OBJECTIVES:Non-celiac wheat sensitivity (WS) is considered a new clinical entity. An increasing percentage of the general population avoids gluten ingestion. However, the real existence of this condition is debated and specific markers are lacking. Our aim was thus to demonstrate the existence of WS and define its clinical, serologic, and histological markers.METHODS:We reviewed the clinical charts of all subjects with an irritable bowel syndrome (IBS)-like presentation who had been diagnosed with WS using a double-blind placebo-controlled (DBPC) challenge in the years 2001–2011. One hundred celiac disease (CD) patients and fifty IBS patients served as controls.RESULTS:Two hundred and seventy-six patients with WS, as diagnosed by DBPC challenge, were included. Two groups showing distinct clinical characteristics were identified: WS alone (group 1) and WS associated with multiple food hypersensitivity (group 2). As a whole group, the WS patients showed a higher frequency of anemia, weight loss, self-reported wheat intolerance, coexistent atopy, and food allergy in infancy than the IBS controls. There was also a higher frequency of positive serum assays for IgG/IgA anti-gliadin and cytometric basophil activation in “in vitro” assay. The main histology characteristic of WS patients was eosinophil infiltration of the duodenal and colon mucosa. Patients with WS alone were characterized by clinical features very similar to those found in CD patients. Patients with multiple food sensitivity were characterized by clinical features similar to those found in allergic patients.CONCLUSIONS:Our data confirm the existence of non-celiac WS as a distinct clinical condition. We also suggest the existence of two distinct populations of subjects with WS: one with characteristics more similar to CD and the other with characteristics pointing to food allergy.

Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines

Objective. Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. Material and methods. Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). Results. When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein–protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. Conclusions. Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

Gastroesophageal reflux and cow's milk allergy in infants : A prospective study

BACKGROUND Recent reports have suggested that gastroesophageal reflux in pediatric patients may be caused by food allergy. OBJECTIVE The aim of our study was to determine the frequency of the association of gastroesophageal reflux with cows milk protein allergy in patients win the first year of life. METHODS We studied 204 consecutive patients (median age, 6.3 months) who had been diagnosed as having gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa. RESULTS Clinical history suggested diagnosis of cows milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus eosinophils) but did not have symptoms indicating cows milk allergy. The cows milk-free diet and two successive blind challenges confirmed the diagnosis of cows milk allergy in 85 of the 204 patients with gastroesophageal reflux. The clinical presentations of the infants with gastroesophageal reflux alone were different, in view of the greater frequency of diarrhea (p less than 0.0001) and atopic dermatitis (p less than 0.0002). In all, gastroesophageal reflux was associated with, and probably caused by cows milk allergy, in 85 of 204 cases (41.8%). CONCLUSIONS Considering the frequency of this association, patients younger than 12 months old with symptoms of gastroesophageal reflux should be carefully examined to determine whether this disorder is primary or caused by cows milk allergy.

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria.

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally.

Intolerance to hydrolysed cow's milk proteins in infants: clinical characteristics and dietary treatment

Multiple food intolerance in infants, including intolerance to extensively hydrolysed proteins (HP), is often difficult to treat. However, few data have been reported on clinical outcome and dietary treatment of these patients.

Lactose Intolerance and Self-Reported Milk Intolerance: Relationship with Lactose Maldigestion and Nutrient Intake

BACKGROUND The relationship between lactose-maldigestion, self-reported milk intolerance and gastrointestinal symptoms has not been clearly defined. OBJECTIVES To evaluate: a) the prevalence of lactose maldigestion and lactose intolerance in a sample of the general population taken from a rural center; b) the frequency of self-reported milk-intolerance and its correlation with lactose-maldigestion; c) the influence of lactose maldigestion, lactose intolerance and self-reported milk intolerance on dietary habits and consumption of total calories, protein, and calcium. SUBJECTS We studied a randomized sample of the general population in a small center in Sicily. 323 subjects (150 males, 173 females), age range 5 to 85 years (median 44) were included and underwent H2-breath test after 25 g lactose load. The preliminary dietary investigation spanned 7 consecutive days using a printed dietary form and was under the daily control of a team of dietitians. METHODS The dietary investigation was completed in the first part of the study and the results were analyzed for nutrient composition by a computerized database. The subjects were then divided into self-reported milk-intolerants and self-reported milk-tolerants and they underwent H2 breath testing; subjects with H2 concentration >20 ppm over the baseline concentration were considered maldigesters and those with one or more symptoms were classified as intolerants. RESULTS 104/323 subjects (32.2%) were lactose maldigesters but tolerants, while 13/323 (4%) were lactose maldigesters and intolerants. In each age-class group (pediatric, adult, and elderly subjects) only the lactose maldigester and intolerant subjects showed differences in nutrient intake with a significantly lower daily consumption of milk and a lower calcium intake. 49/323 subjects were self-reported milk-intolerants; of these, 26 (53%) were lactose maldigesters but tolerants, 18 (37%) were lactose digesters and tolerants and only 5 (10%) were lactose maldigesters and intolerants. In the whole group of self-reported milk-intolerants, dietary milk consumption was significantly reduced and calcium intake was lower than in all the other subjects studied (320 mg/day vs. 585 mg/day, p<0.05). CONCLUSIONS In studies of the general population, the frequency of lactose intolerance is much lower than that of lactose maldigestion. Gastrointestinal symptoms after lactose load in self-reported milk-intolerants are found in only a very low number of these subjects. Furthermore, in these subjects we observed an unnecessary reduction in milk consumption and an insufficient dietary calcium intake.

Nationwide and Long-Term Survey of Primary Glomerulonephritis in Japan as Observed in 1,850 Biopsied Cases

Primary chronic glomerulonephritis is the most common cause of end-stage renal failure in Japan. The incidence in dialysis patients in Japan is about four times higher than in the United States for reason which are unclear. We conducted a nationwide survey on the natural history and treatment of primary glomerulonephritis under a program project from the Ministry of Health and Welfare of Japan entitled ‘Progressive Chronic Renal Disease’. We analyzed patient characteristics, disease onset, clinical data, and histological findings in 1,850 patients with primary glomerulonephritis from 53 institutions in 1985 who underwent renal biopsy at least 5 years ago, and the follow-up study was carried out 8 years after registration. The incidence of diffuse-mesangial proliferative glomerulonephritis is 41.9%, that of minor glomerular abnormalities 17.5%, and that of focal-mesangial proliferative glomerulonephritis 13.0%. Of 1,045 biopsy specimens that were examined by immunofluorescence microscopy, 47.4% showed IgA nephropathy. Half of all cases with primary chronic glomerulonephritis were asymptomatic and were detected on routine health examination. The survival rates at 20 years from the apparent onset or earliest known renal abnormality are: focal glomerular sclerosis 49%, membranoproliferative glomerulonephritis 58%, diffuse-mesangial proliferative glomerulonephritis 66%, focal-proliferative glomerulonephritis 81%, membranous nephropathy 82%, minor glomerular abnormalities 94%, and IgA nephropathy 61%. In conclusion, a high incidence of IgA nephropathy and a better renal survival of membranous nephropathy are the features of primary chronic glomerulonephritis in Japan. This high incidence of IgA nephropathy together with its poor prognosis is probably the reason for the increased incidence of primary chronic glomerulonephritis in dialysis patients in Japan. In addition, the importance of routine health examination including urinalysis is demonstrated.

Sideropenic anemia and celiac disease: one study, two points of view.

Recent studies have pointed to the relationshipbetween iron deficiency anemia and celiac disease,although data on the prevalence of celiac disease inanemic patients have been conflicting, and there is no agreement on the best screening procedurefor CD in these patients. Our aims were to evaluate therelationship between anemia and celiac disease (CD) fromtwo different points of view — the hematology clinic and the pediatric gastroenterologydepartment — and to evaluate the utility ofanti-endomysial antibody determination in screeninganemic patients for CD using human umbilical cord assubstrate. We studied 130 patients with CD (58 males, 72females; median age 18 months) diagnosed at a departmentof Pediatric Gastroenterology, and 85 patients with irondeficiency anemia (38 males, 47 females; median age 48 years) observed at a hematologyoutpatient clinic. From the 85 adult patients with irondeficiency anemia, we selected a subgroup of 25 subjectswith no improvement in Hb after two months of iron therapy (80 mg/day orally). Routinehematochemical tests were performed in all 215 patients.All pediatric and adult subjects underwent immunologicalscreening for celiac disease (AGA and EmA assay);intestinal biopsy was also performed on patients testingpositive. In the adult anemic patients a serum samplewas stored at –20°C on first observation, andafter 6-18 months EmA on human umbilical cord wereassayed. In the pediatric patients with CD, anemia wasobserved in 91/130 patients (70% of cases, the mostfrequent symptom after poor growth); however, this wasthe only presenting symptom of CD in 2/130 patients (1.5% of cases). Anemia was sideropenic in41/91 patients (iron <45 μg/dl, ferritin <15mug/liter). In the adult patients with iron deficiencyanemia, immunological screening (AGA and EmA) showed suspected CD in 5/85 cases (5.8%), withdiagnosis confirmed on intestinal biopsy. These fivepatients were in the subgroup of iron supplementationtherapy nonresponders. CD prevalence in the refractory anemia subgroup was, therefore, 5/25 (20%). Ondiagnosis the hematological indices of the anemia + CDpatients were not different than those of the refractoryanemia patients without CD. The median age of the CD + anemia patients was significantlylower than that of the whole group of anemic subjects,and there was also a prevalence of females (4/5 cases).The results of the EmA determination on human umbilical cord in the adult anemic patientsshowed a perfect concordance with those using atraditional kit that uses monkey esophagus as substrate.In the pediatric age group many cases of CD with anemia as the only sign of the disease are probablynot diagnosed. In our adult patients with sideropenicanemia, CD prevalence was 5-6%; however, the observationof anemic patients not responding to oral iron therapy makes a diagnosis of CD much moreprobable. EmA determination on human umbilical cord isthe most logical approach to screen anemic patients forsuspected CD.