Intestinal permeability in relatives of patients with Crohn's disease

The etiology of Crohn's disease remains unknown, one of theories is the damage of bowel wall with the impairment of small bowel barrier. In patients with Crohn's disease was found high level of small bowel permeability in dependence of disease activity. The aim of our study was to measure small bowel permeability in first-degree relatives of the patients with Crohn's disease. In 14 first-degree relatives of Crohn's disease patients (7 men, 7 women) there was measured small permeability using lactulose, mannitol and D-xylose. Sugars were investigated in 5 hour collected urine and examined using capillary gas chromatography. The absorption of all the sugars--lactulose, mannitol and D-xylose did not differ from healthy controls. The small bowel permeability index (lactulose/mannitol) did not differ from healthy controls too (0.023 vs. 0.019, p = 0.451). These preliminary results confirms the theory, that there is no damage of small bowel barrier in first degree relatives of Crohn's disease patients.     

Intestinal permeability in Crohn's disease patients and their first degree relatives

BACKGROUND: Family studies suggested that an altered intestinal permeability plays a role in the genesis of Crohn's disease. AIM: Aim of the present study was to investigate a possible genetic alteration of the mucosal barrier in Crohn's disease. SUBJECTS: 16 Crohn's disease patients and 26 of their cohabiting first degree relatives were studied. METHODS: To investigate intestinal permeability, Cellobiose/Mannitol test was administered to both groups. RESULTS: In the two groups, we found that the median intestinal permeability values were higher and statistically different from those obtained in 32 healthy control subjects as well as in five healthy control families. Six (37.5%) Crohn's disease patients and three (11.5%) of their first degree relatives showed increased individual intestinal permeability values. Intestinal permeability alteration in Crohn's disease patients was unrelated to sex, age, disease activity, localisation, duration, treatment schedule, as well as to serum anti-Saccharomyces cervisiae antibody positivity in a pilot study conducted in 7 Crohn's disease patients; anti-Saccharomyces cervisiae antibody values were negative in all 10 first degree relatives investigated. CONCLUSIONS: These findings demonstrate the increase in IP in 37% of the patients and in 11% of their relatives. More extensive investigation of the correlation between ASCA alterations and IP will be needed in both patients with Crohn's disease and their relatives.     

Intestinal permeability in patients with Crohn's disease and their first degree relatives.

It has been reported that intestinal permeability to polyethylene glycol 400 is increased in patients with Crohn's disease and their apparently unaffected first degree relatives. Because of the implications that these findings have for the aetiology of Crohn's disease these studies were repeated. Patients with Crohn's disease (n = 28) and 32 first degree relatives from 11 families underwent a polyethylene glycol 400 (PEG400) intestinal permeability test and a hyperosmotic (1500 mosmol/l) absorption/permeability test using 3-0-methyl-D-glucose, D-xylose, L-rhamnose, lactulose, and 51chromium labelled ethylenediamine-tetraacetate. The five hour urine excretion of polyethylene glycol 400 did not differ significantly between controls (n = 25) and first degree relatives, 25.5 (3.3)% v 24.6% (4)% (mean(SD)) p greater than 0.1, respectively. Patients with small bowel involvement excreted significantly less (p less than 0.01) polyethylene glycol 400 (16.3 (4.6)% than controls while those with Crohn's colitis did not (26.4 (3.9)% p greater than 0.1). The permeation of the monosaccharides in patients with Crohn's disease and their first degree relatives did not differ from normal subjects. The permeation of lactulose and 51chromium ethylenediaminetetraacetate was not significantly altered in first degree relatives but was significantly increased in the patients, as was the lactulose/L-rhamnose urine excretion ratio which is a specific measure of small intestinal permeability. These studies show normal absorption and permeability in first degree relatives of patients with Crohn's disease. A genetically determined abnormality of intestinal permeability is not likely to be an important aetiological factor in Crohn's disease.     

Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives.

Increased intestinal permeability in patients with Crohn's disease and their first degree relatives has been proposed as an aetiological factor. The nine hour overnight urinary excretion of polyethyleneglycol-400 (PEG-400) and three inert sugars (lactulose, l-rhamnose, and mannitol) was used to test the permeation in 47 patients with Crohn's disease of whom 18 had at least one first degree relative with inflammatory bowel disease (2BD) and 52 patients with ulcerative colitis of whom 16 had at least one first degree relative with IBD. A total of 17 first degree relatives with IBD and 56 healthy first degree relatives were included. Thirty one healthy subjects not related to patients with IBD served as controls. No significant differences in PEG-400 permeation were found between the groups of patients, relatives, and controls, or between diseased and healthy relatives. The permeability to lactulose, rhamnose, and mannitol similarly did not differ between the three groups. This study challenges the previously reported findings of increased PEG-400 permeation in patients with Crohn's disease and in their healthy and diseased first degree relatives. There was no increase in permeability in a similar group of ulcerative colitis patients and their families.     

Intestinal permeability of 51Cr-labelled ethylenediaminetetraacetic acid in patients with Crohn's disease and their healthy relatives

An increased intestinal permeability has been proposed as an aetiologic factor in Crohn's disease. The 24-h urinary excretion of 100 muCi 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) was used to test the permeability in 15 patients with Crohn's disease and in 20 healthy first-degree relatives, who are known to have a genetic predisposition to inflammatory bowel disease. Twenty-eight healthy persons not related to patients with inflammatory bowel disease served as control material. The 51Cr-EDTA excretion of the relatives (range, 0.98%-3.87%; median, 1.935%) was not significantly higher than that of the controls (range, 1.17%-3.26%; median, 1.950%), whereas patients with Crohn's disease had a significantly higher excretion (range, 1.64%-8.86%; median, 2.940%) than both the relatives and the controls. Among patients the increased excretion was found only if the small intestine was involved. We conclude that 1) as a group, patients with Crohn's disease in the small intestine have an increased intestinal permeability, in contrast to their healthy relatives, who have a normal permeability; 2) a considerable overlap of the results of the 51Cr-EDTA test was found between the groups studied, and the test is not suitable for evaluating individual patients; 3) our results do not support the hypothesis of an increase in intestinal permeability as an aetiologic factor in Crohn's disease.     

Familial Crohn's disease in single or multiple first-degree relatives

The strongest currently recognized risk factor for Crohn's disease (CD) development is having a relative with the disease. In this study, 1,000 patients with CD, seen directly by the investigator during a period of more than 20 years, were consecutively evaluated for a family history of CD. There were 140 patients who reported a relative with CD. Of these, all 87 first-degree relatives were confirmed to have CD (36 men and 51 women). Siblings, particularly women, were most commonly affected in comparison with parents or children. There were 65 with a single affected first-degree relative and 22 with multiple affected first-degree relatives. In this series, the tendency to have a female sibling with CD was further increased in those with multiple affected first-degree relatives. Although the age of diagnosis of children was less than the age of diagnosis in the respective parents, there were almost identical numbers of mother-child and father-child pairs. These findings in a population with prolonged follow-up by the same physician may reflect a bias toward case ascertainment rather than the previously reported phenomena in recruited populations of genetic anticipation and genomic imprinting. Patients with multiple first-degree relatives were older with more extensive disease in both ileal and colonic sites compared with those with only a single first-degree relative and more frequent colonic disease. Future studies are needed to further explore the role of both genetic and environmental factors in the pathogenesis and phenotypic expression of familial CD.     

PEG-400 excretion in patients with Crohn's disease,their first-degree relatives,and healthy volunteers

An altered small bowel permeability may be implicated in the pathogenesis of Crohn's disease. Intestinal permeability, using polyethylene glycol 400 (PEG 400) as the orally ingested probe, was assessed in 45 patients with Crohn's disease (ilealN=14, ileocolonicN=9, colonicN=10, postresectionN=12), 20 first-degree relatives, and 31 controls. PEG 400 excretion was measured using a direct injection HPLC method, and results are expressed as percent of dose recovered in urine (median and range). No quantitative differences in the recovery of PEG-400 were found [Crohn's patients 21.9% (6.1–39.9), relatives 23.7% (4.9–39.9), controls 25.0% (4.5–39.7)]. In all groups, the composition of ingested and recovered PEG-400 was similar and no selective permeability to any molecular weight species was found. Disease site did not influence probe recovery [ileal 23.8% (7.7–30.6), ileocolonic 22.6% (14.4–33.8), colonic 27.8% (9.5–33.5)]. Resected patients had significantly lower PEG-400 recovery [18.8% (8.1–39.9)] than nonresected patients [23.5% (6.1–33.8%)P<0.02]. The data suggest either that altered intestinal permeability is not a factor in Crohn's disease or that PEG-400 is not a suitable probe.     

The obligate anaerobic faecal flora of patients with Crohn's disease and their first-degree relatives

The obligate anaerobic faecal floras of patients with Crohn's disease, their first-degree relatives, and healthy control subjects were compared. The flora of Crohn's patients contained more anaerobic gram-positive coccoid rods and gram-negative rods than that of healthy subjects; on this basis patients and healthy subjects formed two clusters with minor overlap. Nine of 26 children of Crohn's patients were also included within the Crohn's disease cluster. During 5 to 7 years of follow-up study 3 of them presented with remitting abdominal pain, diarrhoea, or weight loss, and in 1 of them Crohn's disease was diagnosed; none of the 17 children with a normal flora showed symptoms possibly due to Crohn's disease. It is concluded that the abnormal flora may be indigenous to subjects predisposed to Crohn's disease, suggesting a direct or indirect relationship between the abnormal faecal flora and Crohn's disease.     

Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease.

The functional integrity of the small bowel is impaired in coeliac disease. Intestinal permeability, as measured by the sugar absorption test probably reflects this phenomenon. In the sugar absorption test a solution of lactulose and mannitol was given to the fasting patient and the lactulose/mannitol ratio measured in urine collected over a period of five hours. The sugar absorption test was performed in nine patients with coeliac disease with an abnormal jejunum on histological examination, 10 relatives of patients with coeliac disease with aspecific symptoms but no villous atrophy, six patients with aspecific gastrointestinal symptoms but no villous atrophy, and 22 healthy controls to determine whether functional integrity is different in these groups. The lactulose/mannitol ratio (mean (SEM) is significantly higher in both coeliac disease (0.243 (0.034), p < 0.0001)) and relatives of patients with coeliac disease (0.158 (0.040), p < 0.005)) v both healthy controls (0.043 (0.006)) and patients with aspecific gastrointestinal symptoms (0.040 (0.011)). The lactulose/mannitol ratio in relatives of coeliac disease patients was significantly lower than in the coeliac disease patient group (p = 0.04). The lactulose/mannitol ratio was the same in healthy controls and patients with aspecific gastrointestinal symptoms. It is concluded that the sugar absorption test is a sensitive test that distinguishes between patients with coeliac disease and healthy controls. The explanation for the increased permeability in relatives of patients with coeliac disease is uncertain. Increased intestinal permeability may be related to constitutional factors in people susceptible to coeliac disease and may detect latent coeliac disease. The sugar absorption test may therefore be helpful in family studies of coeliac disease.     

Elevated basal intestinal mucosal cytokine levels in asymptomatic first-degree relatives of patients with Crohn's disease

AIM To determine levels of cytokines in colonic mucosa of asymptomatic first degree relatives of Crohn's disease patients.METHODS Cytokines (Interleukin (IL) 1-Beta,IL-2, IL-6 and IL-8) were measured using ELISA in biopsy samples of normal looking colonic mucosa of first degree relatives of Crohn's disease patients (n = 9) and from normal controls (n=10) with no family history of Crohn's disease.RESULTS Asymptomatic first degree relatives of patients with Crohn's disease had significantly higher levels of basal intestinal mucosal cytokines (IL-2, IL-6 and IL-8) than normal controls. Whether these increased cytokine levels serve as phenotypic markers for a genetic predisposition to developing Crohn's disease later on, or whether they indicate early (preclinical) damage has yet to be further defined.CONCLUSION Asymptomatic first degree relatives of Crohn's disease patients have higher levels of cytokines in their normal-looking intestinal mucosa compared to normal controls.This supports the hypothesis that increased cytokines may be a cause or an early event in the inflammatory cascade of Crohn's disease and are not merely a result of the inflammatory process.     

Increased antibody response to microbial antigens in patients with Crohn's disease and their unaffected first-degree relatives

Background

Antibodies directed towards bacterial antigens are considered as serological markers of Crohn's disease. Their role in disease pathogenesis is still under investigation.

Aim

Assess the serologic response towards microbial antigens in Crohn's disease patients, their unaffected first-degree relatives and healthy controls.

Methods

This retrospective study included 60 Crohn's disease patients, 86 unaffected first-degree relatives and 100 healthy controls. Their sera were tested for anti-chitobioside, anti-laminaribioside, anti-mannobioside, anti-Saccharomyces cerevisiae and anti-outer membrane porin C of Escherichia coli.

Results

The prevalence of anti-chitobioside and anti-laminaribioside was higher in Crohn's disease patients and their first-degree relatives than in healthy controls (51.67%, 61.63% and 8%, respectively, for anti-chitobioside and 76.17%, 88.37% and 23.00% for anti-laminaribioside; p < 0.0001).The cumulative semiquantitative immune response against all the tested antibodies was higher in unaffected relatives than in healthy controls (p < 0.001).The quantitative analysis revealed that serum levels of anti-chitobioside, anti-laminaribioside and anti-mannobioside were similar in first-degree relatives and Crohn's disease patients and higher than healthy controls (p < 0.001).

Conclusions

Both qualitative and quantitative analysis revealed that unaffected first-degree relatives have increased antibody response to microbial antigens. This impaired immunological response towards enteric microorganisms may result from a genetic predisposition.     

Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease

OBJECTIVE: Increased small intestinal permeability has been found in patients with Crohn's disease and in a proportion of their healthy relatives. This may reflect a shared environment or shared genes. The finding of abnormal permeability in the healthy spouses of patients would favor an environmental cause for this observation. METHODS: The healthy spouses of patients with Crohn's disease attending three gastroenterology clinics were invited to participate. Eligible subjects consumed a 350-ml solution containing lactulose, mannitol, and sucrose before bedtime. All overnight urine was collected, assayed by high performance liquid chromatography, and the ratio of fractional excretion of lactulose to mannitol was calculated as an index of permeability. The results were compared with those of a previously determined control group. RESULTS: Sixty spouses completed the study. Increased permeability was present in eight (13.3%, 95% CI = 6.0-24.6%). The presence of increased permeability was not related to age, gender, duration of cohabitation, alcohol use, nonsteroidal anti-inflammatory drug use or to disease activity in the patient with Crohn's disease. There was a nonsignificant trend for abnormal permeability to occur in those spouses cohabiting with the patient with Crohn's disease at the time of disease diagnosis (p = 0.128). CONCLUSIONS: Small intestinal permeability is increased in a proportion of healthy spouses of patients with Crohn's disease. The presence of abnormal permeability studies in patients with Crohn's disease and a proportion of their healthy close contacts suggests that this phenomenon is caused by environmental factors.     

Genetic and environmental factors in monozygotic twins with Crohn's disease and their first-degree relatives: a case report

BACKGROUND/AIMS: Familial Crohn's disease has shown concordance concerning location and clinical type of the disease especially among monozygotic twins. Susceptibility to Crohn's disease is both based on genetic and environmental factors. We investigated polymorphisms of CARD15, TLR4, and OCTN, and environmental factors in a monozygotic twin pair with Crohn's disease and their first-degree relatives. METHODS: 22-year-old monozygotic female twins with ileocolonic Crohn's disease and their healthy brother and parents were examined. DNA samples from patients and relatives were genotyped for CARD15, TLR4,and OCTN polymorphisms. ASCA and p-ANCA analyses were performed. Additionally, patients and relatives filled out a questionnaire concerning multiple environmental factors. RESULTS: Both twins presented in the same year with identical Vienna Classification phenotypes: stenotic behavior (B2) and localization in terminal ileum and colon (L3). Both carried a CARD15 R702W variant, but had normal alleles in TLR4 and OCTN. They were smokers since the age of 15, used oral contraceptives and had undergone appendectomy. The healthy father and brother were CARD15 R702W positive, were non-smokers and had not undergone appendectomy. CONCLUSION: This case report is the first to describe complete concordance in CARD15 status, phenotypic appearance, and smoking, appendectomy and oral contraceptive use in a pair of monozygotic twins with CD.     

Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor

The cause of Crohn's disease is unknown, although alterations in intestinal permeability may play a primary role. Because we were interested in permeability changes that occur before the onset of intestinal inflammation, we took advantage of the known genetic predisposition to this disease and studied not only patients with Crohn's disease, but their clinically unaffected relatives as well. Intestinal permeability was assessed using the marker polyethylene glycol-400 ingested with a standard meal. We found that 17 normal volunteers absorbed 215 +/- 29.6 mg (mean +/- SE), whereas 11 patients with Crohn's disease absorbed 514 +/- 94.7 mg and their 32 healthy relatives absorbed 566 +/- 62.4 mg. The twofold increase in permeability of patients and their relatives (p less than 0.005 compared with controls) indicates that the intestinal defect in the ability to exclude larger sized molecules is not secondary to clinically recognized intestinal inflammation, but is a primary defect that may be an etiologic factor in this disease.     

Prevalence of gallstone disease in first-degree relatives of patients with cholelithiasis

AIM: To evaluate the influence of familiality on the prevalence of gallstone disease (GD) in Italy. METHODS: Families of 79 subjects with gallstones (cases) and of 79 subjects without gallstones (controls) were investigated for the presence of gallstones by ultrasonography. Index cases and index controls were matched for age, sex, and operative unit. Sixty-three and sixty-two husbands and wives of index cases and index controls, respectively, were also studied. RESULTS: Overall,the prevalence of GD was significantly higher (X2=14.52,P<0.001) in the 202 first-degree relatives of subjects with gallstones than that in the 201 first-degree relatives of subjects without gallstones (28.6% vs 12.4%, relative risk (RR) 1.80, 95% confidence interval (CI) 1.29-2.63). In particular, prevalence of GD was significantly higher in mothers, fathers, and sisters of index cases than that in the respective family members of index controls. The highest RR was observed in mothers (RR=2.35, 95%CI 1.38-4.3). Prevalence of GD was not obviously different in brothers and also in husbands and wives of index cases and index controls. Family members of index cases did not differ from family members of control cases with respect to the most important risk factors for gallstones (age, diabetes, BMI, and number of pregnancies) with an exception of a higher prevalence of diabetes in fathers of index controls than in fathers of index cases. CONCLUSION: This study confirms that familiality plays a very important role in the pathogenesis of gallstones.     

Anti-pancreatic antibody in Turkish patients with inflammatory bowel disease and first-degree relatives

AIM: To identify the role of anti-pancreatic antibody (PAB) in the diagnosis of inflammatory bowel diseases (IBD) among Turkish patients, and its frequency in firstdegree relatives.METHODS: PAB and anti-Saccharomyces cerevisiae (ASCA) were examined in serum samples of 214 subjects including patients with Crohn’s disease (CD, n = 64), ulcerative colitis (UC, n = 63), first-degree relatives of patients with CD (n = 25), first-degree relatives of patients with UC (n = 28),and a control group with gastrointestinal symptoms other than (IBD) (n = 34) by indirect immunofluorescence Positivity of PAB and ASCA was compared in terms of Vienna classification, disease activity and medications used.RESULTS: In terms of PAB positivity, no difference was found between patients with CD (14.1%) and UC (7.9%) however, significant difference was observed between patients with CD and subjects in the control group (P < 0.05). No difference was found between patients with CD and their relatives in terms of ASCA positivity, whereas a significant difference was found between other groups (P < 0.001). Compared to ASCA, the sensitivity of the PAB was 19% (7/37), its specificity was 93% (25/27), positive predictive value was 77% (7/9) and negative predictive value was 45% (25/55). ASCA was found with significantly higher prevalence in patients with CD activity index > 150 (P < 0.05).CONCLUSION: PAB is valuable in the diagnosis of IBD rather than CD, but cannot be used alone for diagnostic purposes. PAB is not superior to ASCA in CD diagnosis and in detecting CD among relatives of patients with CD.     

Intestinal permeability in Crohn's disease and effects of elemental dietary therapy]

Enteral intake of non-metabolic monosacharide and disaccharide, followed by measurement of the urinary excretion ratio of the two, is a method used to investigate intestinal permeability. L/R ratio (lactulose/1-rhamnose urinary excretion ratio) is considered an indicator of permeability of the small intestine. An increased L/R ratio is caused by mucosal disorders of the small intestine. The L/R ratio in all patients (n = 92) with Crohn's disease was 0.079 +/- 0.081 (mean +/- S.D.), which was significantly higher than the value in normal controls (0.027 +/- 0.009, n = 20, p < 0.05). In 39 patients with Crohn's disease, we assessed intestinal permeability before after treatment with an elemental diet, and during remission. The L/R ratio was 0.120 +/- 0.092, before treatment and 0.065 +/- 0.097 after treatment (p < 0.05), showing increased intestinal permeability before elemental dietary treatment. During remission, the L/R ratio was 0.035 +/- 0.028; this did not differ significantly from the value obtained after treatment. We conclude that intestinal permeability is useful for investigating disease activity in patients with Crohn's disease.     

Anticipating response to predictive genetic testing for Alzheimer's disease: a survey of first-degree relatives

Two hundred and three children and siblings of patients with Alzheimer's disease (AD) (age range: 30-92 years, 75% female) were surveyed regarding potential predictive testing options for the disorder. A mailed questionnaire posed various hypothetical scenarios and assessed the following variables: interest in testing, perceptions of its pros and cons, and psychological and demographic predictors of test intentions. In 5 of 6 scenarios, a majority of participants expressed intentions to pursue testing, with perceived pros outweighing cons. The most important reasons for seeking testing were informing later-life decisions and planning future AD care. Predictors of test intentions were male gender, information-seeking style, higher perceived AD threat, and appraisal of test pros versus cons. Situational factors such as available treatment options and certainty of test information also affected responses. Results suggest a positive view of predictive testing, with its limitations and risks underrated. Study findings may inform AD genetic counseling and health education efforts.