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Z M Falchuk

Publications and source records attributed to Z M Falchuk.

At least 37 records · Page 2Linked to original sources
PubMed1978

Gluten-sensitive enteropathy: genetic analysis and organ culture study in 35 families.

The genetic marker histocompatibility antigen HLA-B8 is present in 80% of patients with gluten-sensitive enteropathy (GSE). We studied 35 families with at least one affected member to determine whether an HLA-region gene alone could determine susceptibility to GSE. The incidence of HLA-B8 in the patients was 69% vs 22% for normals (P less than 0.001). The incidence of GSE in HLA-genotype-identical siblings of patients was only 8%, and in HLA-B8-haplotype-identical siblings and parents of patients was only 14% and 5%, respectively. In addition, intestinal biopsies of HLA-identical or partially identical relatives of patients were studied in an in vitro organ culture system capable of detecting gluten sensitivity in subjects ingesting a normal diet. The results confirmed the low incidence of gluten sensitivity in these individuals. The organ culture system could not differentiate mucosa obtained from unaffected parents or siblings of patients with GSE (who presumably carry the HLA-associated genetic information) from mucosa obtained from normals. We conclude that the genetic material inherited with HLA-B8 alone is not sufficient to produce clinical or subclinical disease. Other genetic and environmental factors appear to be important for disease pathogenesis.

Adolescent↗
PubMed1978

Definitive diagnosis of gluten-sensitive enteropathy. Use of an in vitro organ culture model.

The flat mucosal lesion of the small intestine is not pathognomonic of gluten-sensitive enteropathy (GSE). Frequently, the definitive diagnosis of this condition can only be established after three intestinal biopsies are performed: an initial one to show a flat mucosal lesion, one after a gluten-free diet to show morphological recovery, and one after a gluten challenge to show morphological deterioration. We used an organ culture model of GSE to determine the usefulness of this technique in establishing a diagnosis of GSE on the basis of the initial biopsy. Seventy-five patients with diarrhea, and/or malabsorption were evaluated prospectively; 40 had a flat mucosal lesion of variable degree; of these 26 were ultimately determined to have gluten-sensitive enteropathy by the above criteria. A rise in alkaline phosphatase activity of intestinal tissue from 22 of these 26 patients was inhibited when the tissue was cultured in gluten-containing medium as compared to enzyme activities of cultures in a gluten-free medium (108 +/- 69 versus 206 +/- 96, mean +/- SD, P less than 0.001). Mean enzyme values in the similarly cultured intestinal tissue from 13 of 14 patients ultimately shown not to have GSE were not affected by gluten (224 +/- 94 versus 201 +/- 109, P greater than 0.4). Examination of the data by stepwise discriminant analysis provided a function which correctly classified 35 of the 40 patients (88%). The false-positive and false-negative rate for establishing the diagnosis of GSE was 7% (1 of 14) and 15% (4 of 26), respectively. All patients with normal biopsies were classified correctly. The model can be used to establish prospectively the definitive diagnosis of GSE, obviate the need for additional diagnostic biopsies, and allow for the prompt pursuit of alternative diagnoses when gluten sensitivity is not shown.

Adolescent↗
PubMed1976

Gluten-sensitive enteropathy. Inhibition by cortisol of the effect of gluten protein in vitro.

Cortisol partially prevents the harmful effect of gluten on the jejunal mucosa of patients with gluten-sensitive enteropathy. To investigate further the pathogenesis of this disorder, we analyzed the effect of cortisol in cultures of jejunal specimens obtained by biopsy. Cultures were done with and without gluten or cortisol. Morphology and alkaline phosphatase activity were assessed before and after 24 hours. Biopsies from untreated patients cultured with gluten showed low enzyme values and cuboidal epithelial cells before and after culture. Biopsies cultured in a gluten-free medium showed a threefold increase in enzyme values (P less than 0.01) and morphologic improvement with change to columnar epithelial cells. Cultures with gluten plus cortisol showed rises in alkaline phosphatase and morphologic improvement indistinguishable from cultures without gluten. Cortisol and gluten had no effect on cultures from appropriate controls. Cortisol thus prevents the harmful effects of gluten on biopsies from patients with gluten-sensitive enteropathy in vitro.

Adolescent↗
PubMed1976

The coexistence of cystic fibrosis and celiac disease.

Two patients with cystic fibrosis (CF) who subsequently developed celiac disease (CD) are described. Since organ culture of intestinal mucosa has been used to establish an in vitro model for the study of CD, we utilized this opportunity to determine whether duodenal mucosa obtained from each of these two patients and their immediate families differed in its organ culture behavior from mucosa obtained from patients with CD alone. Additionally, as specific HL-A types are associated with CD, we used HL-A typing to determine whether the two patients with CF-CD differed genetically from patients with CD alone. One of our patients was HL-A8, the most common type associated with CD; the other was HL-A12, as are many of the non-HL-A8 celiac patients. The response in organ culture of the mucosa of these two patients was the same as the response in organ culture of the mucosa from patients with CD alone. These and other data suggest that CD occurring in patients with CF is no different than CD occurring alone.

Adolescent↗
PubMed1975

The pathogenesis of gluten-sensitive enteropathy.

Gluten-sensitive enteropathy is characterized by flattening of intestinal villi and malabsorption caused by the toxic effect of gluten, a wheat protein. Gluten activates an endogenous mechanism of toxicity that may be the local mucosal immune system: local mucosal immunoglobulin and antigluten antibody production occur soon after gluten ingestion. Approximately 80% of patients with this disease possess HL-A8, a second segregant series antigen. This association also occurs in dermatitis herpetiformis, a disease with vesicular skin lesions and gluten-sensitive flattening of intestinal villi. The association suggests that the fundamental abnormality in enteropathy is a binding reaction involving gluten protein and a binding site on a cell surface, determined in part by the histocompatibility gene; this reaction then results in a local mucosal immune response to gluten. Alternatively, the fundamental abnormality may be the presence of an abnormal immune-response gene linked to the HL-A8 gene or acting in concert with it; this immune-response gene results in local mucosal production of antigluten antibody.

Adult↗
PubMed1975

Selective immunoglobulin a deficiency, ulcerative colitis, and gluten-sensitive enteropathy--a unique association.

A patient with selective immunoglobulin A deficiency, severe ulcerative colitis, and malabsorption had a flat jejunal mucosa demonstrated by peroral biopsy. Treatment at different times with a gluten-free diet for the jejunal lesion and corticosteroids for the ulcerative colitis, led to improvement of the malabsorption. A repeat jejunal biopsy demonstrated histological improvement of the jejunal mucosa, even though the colitis remained active. The occurrence of immunoglobulin A deficiency in a patient with ulcerative colitis and gluten-sensitive enteropathy is uncommon.

Adrenal Cortex Hormones↗
PubMed1974

Gluten-sensitive enteropathy: synthesis of antigliadin antibody in vitro.

The intestinal mucosa of patients with gluten-sensitive enteropathy responds to gluten challenge in vivo with a striking increase in IgA and IgM synthesis. Whether this increase in immunoglobulin synthesis is due in some part to the production of antigliadin antibodies is examined. Using an affinity chromatography technique it has been demonstrated that in six of seven patients with gluten-sensitive enteropathy approximately half of the net increase in IgA and IgM synthesis occurring after gluten challenge can be attributed to the synthesis of antigliadin antibody. These data strengthen the hypothesis that immunological phenomena are related to the pathogenesis of glutensensitive enteropathy.

Adolescent↗
PubMed1974

An in vitro model of gluten-sensitive enteropathy. Effect of gliadin on intestinal epithelial cells of patients with gluten-sensitive enteropathy in organ culture.

Jejunal biopsy specimens from patients with gluten-sensitive enteropathy (GSE) (obtained during gluten challenge) as well as from normal individuals and patients with other gastrointestinal abnormalities were cultured in vitro for 48 h in the presence or absence of a peptic-tryptic digest (P-T digest) of gliadin. In the absence of gliadin the alkaline phosphatase activity in the biopsy specimens obtained from normal control individuals increased from an initial value of 384 +/- 83 U to a 48 h value of 561 +/- 151 U (mean +/- SD) (difference significant at P < 0.01). The initial alkaline phosphatase activity of specimens obtained from patients with GSE was strikingly lower than that of normals, 117 +/- 79 U, and increased to a 48 h value of 399 +/- 203 U (difference significant at P < 0.01). The biochemical change in cultured biopsy specimens of GSE patients correlated with increases in the length and regularity of brush borders of epithelial cells as seen with the electron microscope. In the presence of a P-T digest of gliadin, the alkaline phosphatase activity of biopsy specimens of control individuals increased from an initial value of 384 +/- 83 U to a 48 h value of 578 +/- 156 U. In contrast, the alkaline phosphatase activity of biopsy specimens of patients with GSE in exacerbation showed a markedly diminished increase in activity during 48 h of culture; in this case the initial activity was 117 +/- 79 U and the final activity was 203 +/- 93 U. This inhibitory effect on increase of alkaline phosphatase activity during organ culture was specific in that a P-T digest of casein (a protein not toxic in vivo to patients with GSE) had no effect on alkaline phosphatase increases in culture. Finally, these results obtained with biopsy specimens taken from patients with GSE in exacerbation were compared with results obtained from patients with GSE in remission. Alkaline phosphatase activity of specimens obtained from the latter group of patients also increased during culture but in this instance P-T digest of gliadin in the culture medium had no significant inhibitory effect. In conclusion, the inhibitory effect of gliadin on intestinal epithelial cells in organ culture represents an in vitro model of gluten-sensitive enteropathy. Inasmuch as this effect of gliadin is not seen in cultures of specimens taken from patients in remission, it appears that gliadin is not directly toxic to GSE jejunal mucosa per se, but rather toxicity requires the participation of an endogenous effector mechanism which must first be stimulated in vivo.

Adolescent↗
PubMed1974

Dermatitis herpetiformis. Immunologic concomitants of small intestinal disease and relationship to histocompatibility antigen HL-A8.

In the present study the relation between the gluten-sensitive intestinal lesion observed in dermatitis herpetiformis (DH) and in gluten-sensitive enteropathy (coeliac sprue) (GSE) was analyzed. Jejunal IgA synthesis in DH was estimated from the extent of incorporation of [(14)C]leucine into IgA in jejunal biopsy specimens during short-term in vitro culture. Patients with DH have significantly elevated incorporation values as compared to normal control individuals (18,880+/-13,614 vs. 5,830+/-3,190 cpm/mg tissue protein/ 90 min) (P < 0.02) and the degree of elevation correlates well with the degree of morphologic abnormality. Thus patients with DH are similar to patients with GSE where elevated local mucosal IgA synthesis has also been observed. By using both morphologic and immunologic criteria for evaluating intestinal status, patients with DH and intestinal disease were distinguished from patients with DH free of intestinal disease. Of the eight patients in the former group, seven carried HL-A8 (87.5%), an incidence which is strikingly similar to that observed in patients with GSE alone (88.5%). In contrast, of the seven patients in the latter group (without gastro-intestinal disease) two had HL-A8, an incidence (27%) not significantly different from that in the normal population (20%) (P > 0.1).Thus, both in respect to local mucosal increase in IgA synthetic rates and in respect to the association with HL-A8, the intestinal lesion of DH is similar to that of GSE.

Adult↗