Milk Protein Sensitive Enteropathy Research Articles

Serum and Tissue CD23, IL‐15, and FasL in Cow's‐Milk Protein–sensitive Enteropathy and in Coeliac Disease

The aim of the study was to explore pathogenesis and find new serum markers for cow's-milk-sensitive enteropathy (CMSE) and coeliac disease (CD). We assessed the intestinal expression and serum concentration of CD23, IL-15, and FasL. We hypothesised that the serum levels of CD23, a protein expressed in the lymphoid follicles, would be associated with lymphonodular hyperplasia (LNH), a feature characteristic of CMSE. We also presumed that interleukin (IL)-15 and FasL, functionally connected with proliferation and apoptosis of the intraepithelial lymphocytes (IELs), would relate with the increased numbers of IELs present in both CMSE and CD. Twenty-three children with CMSE, 20 with untreated CD, and 14 controls were studied for CD3, α/β- and γ/δ-expressing IELs, and for duodenal and ileal expression of CD23, FasL, and IL-15 by immunohistochemistry, and for serum concentration of sCD23, sFasL, and sIL-15 by enzyme-linked immunosorbent assay. There was a trend for increase in sCD23 serum levels in untreated CMSE and in CD (P = 0.074; P = 0.077). CD23 was expressed in the mucosal germinal centres, but sCD23 was not related to presence of LNH. In CMSE, there was a trend for increase in serum sFasL (P = 0.07) and high levels associated with LNH (P = 0.025) and correlated with the IEL numbers (P < 0.05). Mucosal high endothelial venules adjacent to lymphoid follicles showed an intensive FasL expression. Serum sCD23 shows a trend of increment in CMSE and CD, and in the latter, sCD23 level may provide information about the severity of villous atrophy. In CMSE, high serum sFasL indicates both LNH and an increase of IELs, suggesting importance of FasL-mediated mechanisms in the pathogenesis of these features characteristic of CMSE. Further studies are necessary to evaluate whether intensive FasL expression in mucosal high endothelial venules presents a regulatory element in mucosal immunity.

Duodenal cytotoxic lymphocytes in cow's milk protein sensitive enteropathy and coeliac disease

Objective. Pathogenetic mechanisms of cow's milk protein-sensitive enteropathy (CMSE) are poorly defined, but elevated serum granzyme levels and an increase in duodenal intraepithelial lymphocytes (IELs) expressing TIA-1 suggest the involvement of abnormal lymphocyte cytotoxicity. To evaluate cytotoxicity in CMSE we analysed the expression of cytotoxic granule components in duodenal IELs. For comparison, we studied subjects with coeliac disease (CD), in which lymphocyte cytotoxicity is pathogenically important. Material and methods. Fifty-four children were examined by endoscopy for gastrointestinal complaints. Twenty-one subjects had a final diagnosis of CMSE, 15 children had untreated CD and 18 controls showed no definite gastrointestinal disease. Mucosal samples furnished from the bulb and descending duodenum were stained for CD3, perforin, granzymes A and B and TIA-1. Results. In both CMSE and CD, increase of mid-duodenal TIA-1, perforin and granzyme A expressing IELs was seen, the counts in CD being much higher, and increased expression was also seen in the bulb. Granzyme B expression was increased only in CD. In CMSE, no evidence of villous atrophy was seen. Conclusions. Increase in duodenal IELs expressing cytotoxic granules is a characteristic feature in CMSE, although to a lesser degree than in CD. Cytotoxicity is suggested to be involved in the pathogenesis of intestinal dysfunction in CMSE, but based on the absence of villous abnormalities may not be mainly targeted to enterocytes. The mechanisms leading to the accumulation of these cells in CMSE need further investigation.

Serum granzymes and CD30 are increased in children's milk protein sensitive enteropathy and celiac disease

Cow's milk protein sensitive enteropathy (CMSE) and celiac disease (CD) associate with upregulation of local intestinal immune responses, including activation of cytotoxic lymphocytes. We investigated whether this upregulation can be detected at the systemic level by analyzing serum concentrations of granzymes A (GrA) and B (GrB), soluble Fas, and CD30. Fifty-seven children with a final diagnosis of CMSE in 23 subjects (18 untreated and 5 on a diet), 20 untreated CD patients, and 14 control subjects with no gastrointestinal disease were examined by endoscopy for gastrointestinal complaints. Duodenal biopsies were studied for basic histology, CD3, alphabeta and gammadelta T-cell receptors (TCRs), and serum samples by commercial ELISA assays. Concentrations of GrA and GrB were significantly higher in untreated CMSE and in CD as compared with the control subjects. Measurable GrB was present in only 20% of the control subjects but in 100% of patients with CMSE. CD30 was similarly increased in both untreated CMSE and CD cases, whereas in treated CMSE cases the concentrations were equal to the control subjects. All groups showed similar soluble Fas. The numbers of duodenal CD3 + , alphabeta- and gammadelta-TCRs correlated with the serum granzyme and CD30 levels. The intestinal immune response in CMSE and CD is manifested by the increase in serum GrA, GrB, and CD30; the measurement of these markers provides a new practical and objective complementary means for diagnosis and assessment of treatment response. However, this has to be confirmed by more studies before routine use.

Cow's milk protein-sensitive enteropathy at school age

Objectives: Cow's milk protein-sensitive enteropathy (CMSE) may persist in children to school age. We sought to define the morphologic and immunohistochemical features of persistent CMSE. Study design: We studied 15 children with a definite diagnosis of CMSE on the basis of a blind challenge, 12 children with suspected cases of CMSE, 11 children with celiac disease, and 12 control children. Results: Typical findings in children with CMSE were endoscopically visible lymphonodular hyperplasia of the duodenal bulb and lymphoid follicles without villous atrophy in biopsy samples. The patients with definite CMSE showed significantly increased densities of intraepithelial T cells skewed clearly to γδ + cells, compared with the control patients but fewer than in the patients with celiac disease. The study children showed no aberrant upregulation of HLA-DR expression in the duodenal mucosa, and the prevalence of HLA DQ2 antigen among them was equal to that in the control children. Conclusions: Our observations corroborated the claim that CMSE at school age is an identifiable clinical entity. Immunohistochemical findings suggest the abrogation of antigen tolerance locally on the gastrointestinal mucosa. A careful clinical assessment that includes a long elimination–challenge test supported by typical endoscopic and histologic findings form the basis for diagnosis. (J Pediatr 2001;139:797–803)

Cow's milk protein-sensitive enteropathy at school age: A new entity or a spectrum of mucosal immune responses with age

Cow's milk protein-sensitive enteropathy at school age: A new entity or a spectrum of mucosal immune responses with age

Is Cow's Milk Protein Sensitive Enteropathy a Cell Mediated Immunological Phenomenon?

Is Cow's Milk Protein Sensitive Enteropathy a Cell Mediated Immunological Phenomenon?

Zöliakie als Ursache für Dünndarmverschluß

We report the case of a 13 month old boy presenting with an intestinal pseudo-obstruction. He showed the clinical and radiological features typical of a paralytic intestinal occlusion. After 48 hours of parenteral nutrition, the intestinal motility returned to normal. A jejunal biopsy showed total villous atrophy. The patient did not relapse with the same symptoms on a gluten challenge. The differential diagnosis and the similarities with obstructive events in cow's milk protein sensitive enteropathy are discussed.

Rectal mucosa in cows' milk allergy.

Eleven infants who were suspected clinically of having cows' milk protein sensitive enteropathy were fed with a protein hydrolysate formula for six to eight weeks, after which they had jejunal and rectal biopsies taken before and 24 hours after challenge with cows' milk protein. When challenged six infants (group 1) developed clinical symptoms and five did not (group 2). In group 1 the lesions developed in both the jejunal mucosa (four infants at 24 hours and one at three days), and the rectal mucosa, and the injury was associated with depletion of alkaline phosphatase activity. Infants in group 2 were normal. It seems that rectal injury that develops as a direct consequence of oral challenge with the protein in reactive infants may be used as one of the measurements to confirm the diagnosis of cows' milk protein sensitive enteropathy. Moreover, ingestion of such food proteins may injure the distal colonic mucosa without affecting the proximal small gut in some infants.

Severity and extent of upper small bowel mucosal damage in cow's milk protein-sensitive enteropathy.

A series of 31 infants, 28 with cow's milk protein sensitive enteropathy (CMPSE) and 3 controls, was studied for severity and extent of mucosal damage of the upper small bowel in relation to the development of clinical symptoms. Following challenge with the offending cow's milk, 18 infants (Group 1) developed severe mucosal changes at both the proximal and distal small bowel mucosa and all of these infants presented with clinical symptoms. The other 10 infants (Group 2) who did not develop clinical symptoms following the challenge had less severe damage to the distal small bowel mucosa as compared to the proximal region. The histological score of both the proximal and distal postchallenge biopsies were significantly lower in Group 2 as compared to Group 1 infants. The mucosal disaccharidase and alkaline phosphatase levels were depleted in both the proximal and distal biopsies following challenge but the depletion was greater in the proximal than the distal biopsies. It is suggested that the extent and severity of mucosal damage to the proximal duodenum and jejunum have a critical bearing on the development of clinical symptoms.

Severity and Extent of Upper Small Bowel Mucosal Damage in Cow's Milk Protein‐Sensitive Enteropathy

SummaryA series of 31 infants, 28 with cow's milk protein sensitive enteropathy (CMPSE) and 3 controls, was studied for severity and extent of mucosal damage of the upper small bowel in relation to the development of clinical symptoms. Following challenge with the offending cow's milk, 18 infants (Group I) developed severe mucosal changes at both the proximal and distal small bowel mucosa and all of these infants presented with clinical symptoms. The other 10 infants (Group 2) who did not develop clinical symptoms following the challenge had less severe damage to the distal small bowel mucosa as compared to the proximal region. The histological score of both the proximal and distal postchallenge biopsies were significantly lower in Group 2 as compared to Group I infants. The mucosal disaccharidase and alkaline phosphatase levels were depleted in both the proximal and distal biopsies following challenge but the depletion was greater in the proximal than the distal biopsies. It is suggested that the extent and severity of mucosal damage to the proximal duodenum and jejunum have a critical bearing on the development of clinical symptoms.

Effect of diet on the clinical course and repair of the small bowel mucosa in infantile gastroenteritis

The effect of cow milk protein (CMP), soy protein (SP) and protein hydrolysate formula (PHF), on clinical and mucosal recovery was studied in 26 infants with acute gastroenteritis associated with acquired carbohydrate intolerance.Following rehydration the infants were regraded onto cows' milk. Of seven infants intolerant to the CMP six did not tolerate lactose‐free CMP and SP but thrived on PHF; the other infant was intolerant to lactose‐free CMP but accepted the SP. Of another 12 infants intolerant to CMP, eight tolerated SP and four did not but thrived on PHF. Seven other young infants who presented with severe clinical symptoms were placed directly on PHF. Biopsies were performed at initial illness, during the illness and following clinical recovery. The infants had a damaged mucosa while on an intolerant formula. The disaccharidase levels of the biopsy were low during the initial illness but increased rapidly during the recovery period. Rapid clinical and mucosal recovery was observed in nine infants who tolerated SP and 17 infants on PHF.CMP challenge was conducted in 26 infants and 16 infants had cows' milk protein sensitive enteropathy (CMPSE) indicating that CMPSE was the basis for the persistent diarrhoea and impaired mucosal recovery in these 16 infants. The role of food protein sensitive enteropathy and other factors influencing the clinical course and mucosal recovery in young infants with acute gastroenteritis is discussed.

Effect of continued feeding of cows' milk on asymptomatic infants with milk protein sensitive enteropathy.

The clinical response and the histological changes in the mucosa of the small bowel in response to continued feeding with cows' milk protein were assessed over a period of 2-6 weeks in 24 infants who had shown histological changes without immediate clinical symptoms after challenge with a diet containing cows' milk protein. Twenty of the 24 infants (83%) thrived well on cows' milk protein. Jejunal biopsy specimens taken six to eight weeks after the initial biopsy showed histological improvement in all 20 infants compared with biopsy specimens taken soon after the challenge, which had shown mucosal damage. The mucosa had returned to normal in 12, was mildly abnormal in seven, and moderately abnormal in one. Corresponding improvements in the activities of mucosal enzymes were seen. In four of the 24 infants (17%) symptoms developed between three and six weeks. Histological examination of the jejunal biopsy specimens showed that mucosal damage had progressed in two, and remained the same in two; moreover, the disaccharidase activities remained depressed. The present study shows that most infants with enteropathy caused by sensitivity to cows' milk protein but without clinical symptoms develop tolerance to the protein and the mucosa returns to normal despite continued feeding with cows' milk protein.

Cowʼs Milk Protein-Sensitive Enteropathy

Summary: Intestinal biopsy is an essential procedure in the diagnosis of cow's milk protein-sensitive enteropathy. The number and timing of biopsies, however, is still controversial. Twenty-two infants who were clinically suspected of having cow's milk protein intolerance were put on a milk-free diet, during which they all improved. In the first 14 infants (Group I), milk withdrawal lasted 6-8 weeks; in the following 8 infants (Group II), milk withdrawal lasted 3.5-4 months. At the end of the withdrawal period, each patient was submitted to an oral lactose tolerance test and then to a first jejunal biopsy, followed by a cow's milk challenge, and a second biopsy (1-2 days later). None of the infants showed evidence of lactose intolerance, but they all reacted adversely to milk reintroduction. In Group I, the distribution of mucosae from grade 0 (normal) to III was almost the same before and after challenge (p > 0.5); this is considered to be due to the severe mucosal damage still present in prechallenge biopsies. In Group II, however, a significant difference was found in the distribution of mucosae before and after challenge (p < 0.05), and a deterioration could be observed in each case after challenge. Intraepithelial lymphocyte counts and mitotic index determinations before and after milk reintroduction were of no diagnostic value in either group. It is suggested that the diagnosis of cow's milk protein-sensitive enteropathy may rely on two biopsies, the first after a period of 3.5-4 months on milk-free diet and the second following milk challenge.

Cowʼs Milk Protein-Sensitive Enteropathy

Intestinal biopsy is an essential procedure in the diagnosis of cow's milk protein-sensitive enteropathy. The number and timing of biopsies, however, is still controversial. Twenty-two infants who were clinically suspected of having cow's milk protein intolerance were put on a milk-free diet, during which they all improved. In the first 14 infants (Group I), milk withdrawal lasted 6-8 weeks; in the following 8 infants (Group II), milk withdrawal lasted 3.5-4 months. At the end of the withdrawal period, each patient was submitted to an oral lactose tolerance test and then to a first jejunal biopsy, followed by a cow's milk challenge, and a second biopsy (1-2 days later). None of the infants showed evidence of lactose intolerance, but they all reacted adversely to milk reintroduction. In Group I, the distribution of mucosae from grade 0 (normal) to III was almost the same before and after challenge (p greater than 0.5); this is considered to be due to the severe mucosal damage still present in prechallenge biopsies. In Group II, however, a significant difference was found in the distribution of mucosae before and after challenge (p less than 0.05), and a deterioration could be observed in each case after challenge. Intraepithelial lymphocyte counts and mitotic index determinations before and after milk reintroduction were of no diagnostic value in either group. It is suggested that the diagnosis of cow's milk protein-sensitive enteropathy may rely on two biopsies, the first after a period of 3.5-4 months on milk-free diet and the second following milk challenge.

Cow's milk protein-sensitive enteropathy (CMPSE) in infant with chronic diarrhea.

Six cases of CMPSE as revealed by biopsy studies and clinical symptoms are presented. All infants suffered from chronic diarrhea, of which 5 developed failure to thrive. No pathogenic microorganism was isolated from the stools. Stool ova and parasites were also negative. Lactose intolerance was not found among these infants. The possible pathogenesls has been briefly discussed. The present series obviously indicates that CMPSE does occur in Indonesia.

Gastroenterological and immunological aspects of cow's milk protein sensitive enteropathy.

CMPI is a 20 th century disease. Until fairly recently it was not possible to feed safely large numbers of young infants other than by human breast milk. In our time, however, cow's milk protein is quantitatively the most important dietary protein in young infants.

In vitro diagnosis of cow's milk protein sensitive enteropathy by organ culture method.

The criteria that are used at present to diagnose cow's milk protein sensitive enteropathy (CMPSE) are based on an in vivo milk challenge which can be hazardous and life threatening. We have used an organ culture model to determine the usefulness of this technique in establishing the diagnosis of CMPSE on the basis of a single biopsy with in vitro milk challenge. Fourteen infants with diarrhoea clinically suspected to have CMPSE were studied prospectively. On the basis of milk challenge studies seven infants had CMPSE. They had clinical reaction to cow's milk with associated histological changes and depression of alkaline phosphatase levels in the jejunal mucosa. In all seven cases parallel changes in alkaline phosphatase levels were noted in the organ culture specimens of initial biopsy subjected to in vitro challenge. The seven control infants tolerated cow's milk and did not have histological changes. The alkaline phosphatase levels were moderately increased in the jejunal mucosa in five of the seven infants. The alkaline phosphatase levels in the organ culture specimens of initial biopsy were increased after in vitro challenge in all seven infants. This study suggests that organ culture methods may be useful in the vitro diagnosis of CMPSE, and also obviate the need for in vivo oral milk challenges and repeated biopsies.

Immunological studies in cows' milk protein-sensitive enteropathy.

55 infants, aged between 1 and 13 months, who presented with persistent diarrhoea were placed on a diet free of cows9 milk protein. The clinical condition of the infants improved and 6-8 weeks later each was challenged with low-lactose cows9 milk. The following investigations were performed before and 24 hours after provocation: jejunal biopsy, serum and duodenal juice levels of complement C3 and C4, C3-activator, and immunoglobulins A, G, M, and D. Three groups were recognised on postchallenge clinical symptoms together with histological changes in the jejunal mucosa: group 1 (n=10 infants) with no clinical or mucosal abnormality, group 2 (n=18 infants) with mucosal abnormalities but lacking clinical symptoms, and group 3 (n=27 infants) with mucosal abnormalities and clinical symptoms; but in group 3 symptoms were delayed for over 24 hours in 7 infants, and in the remaining 20 infants symptoms appeared within 24 hours. After provocation the serum IgG levels were decreased in 3 infants in group 1, 12 in group 2, and 17 in group 3. The mean serum IgA and IgM levels were higher in group 1 compared with group 2 or 3; pre- and postchallenge mean serum immunoglobulin levels, complement, and complement activator levels were of equal magnitude in all three groups. A depletion of serum complement C3 level was observed in 4 (group 1), 4 (group 2), and 13 (group 3) infants 24 hours after provocation with cows9 milk; the fall in serum IgG was often associated with depletion of complement in serum. This suggests the involvement in some infants of IgG-mediated complement-consuming immune reactions in the development of the damage in the intestinal mucosa. After challenge, exudation of IgG and IgA occurred irrespective of the presence or absence of mucosal damage and was not always associated with the decrease in serum IgG concentration. Because of the variable conditions present in the intestinal lumen it is suggested that the level of immunoglobulins in duodenal juice is not a reliable measure of the local immune response. Levels of complement and immunoglobulin in serum or duodenal juice fail to provide help in the diagnosis of cows9 milk protein-sensitive enteropathy.

Cows' milk protein-sensitive enteropathy

Cows' milk protein-sensitive enteropathy

Cow's milk protein sensitive enteropathy (CMPSE): an important cause of protracted diarrhoea in infancy.

Iyngkaran, N., Robinson, M. J., Davis, K. A., Sumithran, E., Kumar, M. V., Ong, T. H., Yadav, M., Boey, C. G., Lam, S. K. and Puthucheary, S. D. (1979). Aust. Paediatr. J., 15, 266–270. Cow's milk protein sensitive enteropathy (CMPSE): an important cause of protracted diarrhoea in infancy. Twenty‐six infants with protracted diarrhoea were studied, and 21 were found to have cow's milk protein sensitive enteropathy. Associated secondary sugar intolerance was present in the majority of these infants, but the symptoms did not improve with a lactose‐free, cow's milk protein containing formula. Eleven infants tolerated and thrived well on a lactose and cow's milk protein‐free formula. Ten infants required total parenteral nutrition for periods of 1 to 3 weeks before they tolerated a lactose and cow's milk protein‐free formula orally. This limited study suggests that cow's milk protein sensitive enteropathy may be a major cause of protracted diarrhoea in infancy and that exclusion of cow's milk protein as well as lactose from the diet is essential in the nutritional rehabilitation of these infants. With careful manipulation of these special formulae the need for total parenteral nutrition may be obviated in many infants with protracted diarrhoea.