Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential.

The small intestinal (SI) epithelium harbors a heterogeneous population of lymphocytes that mediate mucosal damage and repair in celiac disease (CD). The composition and roles of human proximal SI intra-epithelial innate lymphoid cells (ILCs), and their alterations in CD, are not well understood. We report that duodenal intra-epithelial ILCs predominantly consist of natural killer (NK)p44+ CD127- cytotoxic ILC1s and NKp44- CD127+ helper ILC1s, while ILC3s only represent a minor population. In patients with newly diagnosed or active CD (ACD) and refractory CD type 1 (RCD I), the frequency of SI NKp44+ ILCs is decreased, with restoration of NKp44+ ILC frequency observed in patients adhering to a gluten-free diet who show evidence of mucosal healing. Moreover, the frequency of SI NKp44- ILCs is increased in ACD and RCD I patients and correlates with the severity of villous atrophy and epithelial damage, as assessed by serum levels of fatty acid binding protein 2 (FABP2). We show that the ILC alterations in CD represent a phenotypic shift of cytotoxic ILC1s rather than an increase in helper ILC1s or transdifferentiation of ILC1s to ILC3s, and activation-induced loss of NKp44 by cytotoxic ILC1s is associated with increased interferon (IFN)-γ expression and release of lytic granules. These findings suggest that intra-epithelial NKp44- CD127- cytotoxic ILC1s may contribute to mucosal damage in CD.

Portable gluten sensors: qualitative assessments by adults and adolescents with coeliac disease.

BACKGROUND: Portable gluten sensors are now commercially available to the public, although there is genuine uncertainty within the medical community over whether they should be used for coeliac disease management. The present study described qualitatively the experience of using a portable gluten sensor for 15 adults and 15 adolescents with coeliac disease participating in a 3-month pilot clinical trial. METHODS: Participants were 30 individuals, aged 13-70 years, with biopsy-confirmed coeliac disease on a gluten-free diet. All received a portable gluten sensor and were randomised to low, medium, and high numbers of single-use capsules. Open-ended questions addressed likes and dislikes using the portable gluten sensor after 3 months. Major themes were identified and described. RESULTS: Participants liked that the portable gluten sensor provided extra assurance to check foods presented as gluten-free, the convenient size and portability, the added sense of control, and overall peace-of-mind. Participants disliked having attention drawn to them when using the sensor and feeling as if they were deterring others from eating. Participants also disliked the physical difficulty associated with using the capsules, questionable accuracy and the inability to test fermented foods. Adults were more enthusiastic about the sensor than adolescents. CONCLUSIONS: Positive and negative experiences may be expected when using commercially available portable gluten sensors to help manage coeliac disease. As future versions of this and other gluten sensors become available, it will be important to investigate the relationship between users' experience with the sensors and long-term outcomes such as mucosal healing and quality of life.

Diminished quality of life among adolescents with coeliac disease using maladaptive eating behaviours to manage a gluten-free diet: a cross-sectional, mixed-methods study.

BACKGROUND: Certain approaches to managing a strict gluten-free diet (GFD) for coeliac disease (CD) may lead to impaired psychosocial well-being, a diminished quality of life (QOL) and disordered eating. The present study aimed to understand adolescents' approaches to managing a GFD and the association with QOL. METHODS: Thirty adolescents with CD (13-17 years old) following the GFD for at least 1 year completed the Celiac Dietary Adherence Test (CDAT) and QOL survey. Their approaches to GFD management were explored using a semi-structured interview, where key themes were developed using an iterative process, and further analysed using a psychosocial rubric to classify management strategies and QOL. CDAT ratings were compared across groups. RESULTS: Gluten-free diet management strategies were classified on a four-point scale. Adaptive eating behaviours were characterised by greater flexibility (versus rigidity), trust (versus avoidance), confidence (versus controlling behaviour) and awareness (versus preoccupation) with respect to maintaining a GFD. Approximately half the sample (53.3%) expressed more maladaptive approaches to maintaining a GFD and those who did so were older with lower CD-Specific Pediatric Quality of Life (CDPQOL) scores, mean subscale differences ranging from 15.0 points for Isolation (t = 2.4, P = 0.03, d.f. = 28) to 23.4 points for Limitations (t = 3.0, P = 0.01, d.f. = 28). CONCLUSIONS: Adolescents with CD who manage a GFD with maladaptive eating behaviours similar to known risk factors for feeding and eating disorders experience diminished QOL. In accordance with CD management recommendations, we recommend ongoing follow-up with gastroenterologists and dietitians and psychosocial support referrals, as needed.

Persistent mucosal damage and risk of epilepsy in people with celiac disease.

BACKGROUND AND PURPOSE: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. METHODS: This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. RESULTS: Villous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). CONCLUSIONS: In a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

Coeliac disease: the association between quality of life and social support network participation.

BACKGROUND: There is little information available on the use of social support systems for patients with coeliac disease (CD). We performed a cross-sectional study aiming to examine the association between participation in different types of social support networks and quality of life (QOL) in adults with CD. METHODS: A survey including a validated CD specific QOL instrument was administered online and in-person to adults with CD who were following a gluten-free diet. Participation in social support networks (type, frequency and duration) were assessed. RESULTS: Among the 2138 participants, overall QOL scores were high, averaging 68.9 out of 100. Significant differences in QOL scores were found for age, length of time since diagnosis and level of education. Most (58%) reported using no social support networks. Of the 42% reporting use of social support networks (online 17.9%, face-to-face 10.8% or both 12.8%), QOL scores were higher for those individuals who used only face-to-face social support compared to only online support (72.6 versus 66.7; P < 0.0001). A longer duration of face-to-face social support use was associated with higher QOL scores (P < 0.0005). By contrast, a longer duration and increased frequency of online social support use was associated with lower QOL scores (P < 0.03). CONCLUSIONS: Participation in face-to-face social support networks is associated with greater QOL scores compared to online social support networks. These findings have potential implications for the management of individuals with CD. Emphasis on face-to-face support may improve long-term QOL and patient outcomes.

Living with coeliac disease: survey results from the U.S.A.

BACKGROUND: The only treatment for coeliac disease is lifelong adherence to a rigorous gluten-free diet. The present study aimed to evaluate the influence of coeliac disease on the social aspects of daily life of individuals in the U.S.A. METHODS: The present study used a self-administered survey including the standard Quality of Life questionnaire (12-item short-form) with validated disease-specific questions. sas statistical software 2010 (SAS Institute, Cary, NC, U.S.A.) was used to calculate the mean (SD). RESULTS: Individuals with coeliac disease overall had a low positive health perception. Validated diet and disease-specific questions revealed a significant negative impact on quality of life in social settings. Specifically, the areas of travel, dining out and family life are most affected. The negative impact of diet significantly decreased over time, although it did not resolve for the domains of dining out of the home and travel. Those diagnosed in childhood and maintained on the diet had less of an impact on the quality of life as an adult. CONCLUSIONS: Individuals with coeliac disease in the U.S.A. have a diminished quality of life, especially in the social aspects of life.

Clinical management of coeliac disease.

OBJECTIVE: To describe the prevalence of Coeliac disease (CD) and its clinical management. METHODS: Narrative review. RESULTS: Coeliac disease (CD) is an immune-mediated disorder that primarily affects the gastrointestinal (GI) tract. Recent data suggest a prevalence of about 1% in most Western countries, a figure that likely represents an increase in the prevalence of CD. Risk groups include those who are members of families with individuals who have CD as well as those with Type I diabetes and a variety of autoimmune diseases. Whereas biopsy is the gold standard in diagnosis, serological tests are crucial in determining who should undergo endoscopy and biopsy. HLA testing should be used only to rule out CD. Currently, a gluten-free diet is the only available therapy. CONCLUSION: In conclusion, CD is one of the most common immune-mediated disorders in the Western world. It should be considered in patients with a number of varying GI and non-GI symptoms, as well as in high-risk groups that include first-degree relatives.

The effect of substituting alternative grains in the diet on the nutritional profile of the gluten-free diet.

BACKGROUND: The only treatment for coeliac disease is lifelong adherence to a gluten-free diet. Several studies have reported nutritional deficiencies in individuals on a gluten-free diet. The present study aimed to determine whether the nutritional profile of gluten-free diet could be improved through the use of alternative grains. METHODS: A retrospective review of diet history records by a celiac specialist dietitian were used to establish a 'standard' gluten-free dietary pattern. An 'alternative' gluten-free dietary pattern was developed that substituted naturally gluten-free grains or gluten-free products made from 'alternative' flours (oats, high fibre gluten-free bread and quinoa) in the standard pattern. A paired t-test was performed to identify statistical significance between the 'alternative' and standard gluten-free dietary pattern. RESULTS: Analysis of standard pattern indicated that 38% of meals and snacks contained no grain or starch choice. Of those meals that contained a grain or starch component, rice was the grain chosen 44% of the time. The inclusion of alternative grains or grain products provided a higher nutrient profile compared to the standard gluten-free dietary pattern (P = 0.002). Several nutrients; protein (20.6 g versus 11 g), iron (18.4 mg versus 1.4 mg), calcium (182 mg versus 0 mg) and fibre (12.7 g versus 5 g) were significantly increased by changing the grain or starch component in the dietary pattern. The B vitamin content (riboflavin, niacin and folate) was improved, although this was not statistically significant (P = 0.125). DISCUSSION: The inclusion of alternative grain-based products increased the nutrient profile of the gluten-free dietary pattern significantly.

Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease.

BACKGROUND: Cerebellar syndrome and small fiber neuropathy may complicate celiac disease (CD) and may be resistant to a strict gluten-free diet. METHODS: Case series. RESULTS: We report three patients with biopsy-proven CD who developed cerebellar ataxia and neuropathic pain despite strict adherence to a gluten-free diet. A small fiber neuropathy was suggested by skin biopsy findings in two patients. All patients' symptoms, including small fiber neuropathy symptoms, responded to treatment with intravenous immunoglobulin (IVIG). Discontinuation of IVIG in two patients resulted in worsened ataxia that reversed after resumption of IVIG. CONCLUSION: Intravenous immunoglobulin may be effective in treating cerebellar ataxia and small fiber neuropathy associated with CD, suggesting an immune pathogenesis. Further prospective, controlled studies are necessary to determine the long-term response to IVIG or other immunomodulation therapy.

Systematic review with meta-analysis: the prevalence of coeliac disease in patients with osteoporosis.

BACKGROUND: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis. AIMS: To investigate the prevalence of CD among individuals with osteoporosis. METHODS: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with "fractures", "bone disease", "bone density", "densitometry", "osteoporos*", "osteomal*", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English-language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression. RESULTS: We identified eight relevant studies, comprising data from 3188 individuals with osteoporosis. Of these, 59 individuals (1.9%) had CD. A weighted pooled analysis demonstrated biopsy-confirmed CD in 1.6% (95% CI = 1.1%-2.0%) of individuals with osteoporosis. The heterogeneity was moderate (I2  = 40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n = 814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI = 1.2%-2.0%). CONCLUSIONS: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs.

Rat intestine secretes discoid high density lipoprotein.

High density lipoprotein was isolated from pooled rat serum and mesenteric lymph of lymph fistula rats. In most experiments, 5,5'-dithionitrobenzoic acid, an inhibitor of the enzyme lecithin:cholesterol acyltransferase, was added during the collection of lymph to prevent modification of the lipid composition of newly secreted lipoproteins. Negative staining electron microscopy of lymph high density lipoprotein revealed discoidal particles (190+/-3 x 55+/-1 A) which tended to form rouleaux, smaller spherical particles were also present. Serum high density lipoprotein contained only spherical particles (diameter 93+/-4 A). Lipid analysis showed that lymph high density lipoprotein was enriched in phospholipid and deficient in cholesterol esters when compared to serum high density lipoprotein. The phospholipid to cholesterol esters ratio was greatest in basal lymph high density lipoprotein when compared to fatty lymph and serum high density lipoprotein. From analysis of the lipid compositional data and direct particle measurement by electron microscopy, it could be determined that congruent with50% of basal lymph high density lipoprotein and 30% of fatty lymph high density lipoprotein was discoid. Basal lymph high density lipoprotein was enriched in apoA-I and deficient in the arginine-rich peptide, and the apoprotein composition of fatty lymph high density lipoprotein more closely resembled serum. These observations demonstrate that intestinal lymph contains two types of high density lipoprotein particles, a discoid nascent particle deficient in cholesterol ester and rich in apoA-I, and spherical high density lipoprotein derived from plasma. A significant amount of lymph high density lipoprotein appears to be secreted by the intestine.

Metabolic fate of chylomicron phospholipids and apoproteins in the rat.

To study the metabolic fate of chylomicron phospholipid and apoproteins, 15 mg of doubly labeled ([(3)H]leu, [(32)P]phospholipid) rat mesenteric lymph chylomicrons were injected as an intravenous bolus into conscious rats. The specific radioactivity, composition, pool size, and morphology of the plasma lipoproteins were determined after 2-60 min. After injection of chylomicrons, there was a rapid transfer of radioactivity into high density lipoproteins (HDL). At peak specific activity in HDL (2-5 min), 35% of injected apoprotein and 25% of phospholipid radioactivity were recovered in HDL (d 1.063-1.21 g/ml), with smaller recoveries in other lipoproteins and liver. There was an initial rapid rise of (32)P specific activity in HDL and d 1.02-1.063 lipoproteins (low density lipoproteins [LDL]), but whereas LDL specific activity subsequently converged with that of d < 1.02 lipoproteins, HDL specific activity decayed more rapidly than LDL or d < 1.02 lipoproteins. Lipolysis of chylomicrons was associated with a transfer of phospholipid mass into LDL and HDL. At 5 min, 80% of injected triglyceride had been lipolyzed and there was a significant increase in phospholipid mass in LDL and a smaller increase in HDL. At 10 min, the mass of phospholipid in LDL had returned towards control values, and there was a further increase in phospholipid mass in HDL, which suggested phospholipid transfer from LDL to HDL. In donor lymph chylomicrons (3)H-radioactivity was present in apoprotein (apo)B, apoA-I, and apoA-IV, but only radioactivity of apoA-I and apoA-IV were transferred to HDL. Transfer of radioactivity was associated with loss of mass of apoA-I and apoA-IV from the fraction that contained the chylomicron remnants (d < 1.02). With injection of 15 mg chylomicron, there was a small but insignificant increase in the relatively large pool of HDL apoA-I. However, 60 min after injection of 250 mg of human or rat intestinal chylomicrons into the rat, there was a significant increase in HDL apoA-I that resulted from acquisition of a major fraction of the chylomicron apoA-I. After injection of chylomicrons, phospholipid vesicles were observed by negative stain electron microscopy in the LDL and HDL ultracentrifugal fractions, especially in the LDL. Upon addition of an osmotically active compound, cellobiose, vesicles were observed as flattened particles with a double lipid bilayer thickness ( congruent with 100 A). To validate further the identity of these particles, chylomicrons were injected into rats with [(3)H]glucose, and the recipient rats' plasma was fractionated by chromatography on 6% agarose. Trapping of [(3)H]glucose occurred in the void and LDL regions of the column, and vesicular particles were identified in these column fractions by negative stain electron microscopy. Catabolism of chylomicrons is associated with a rapid transfer of phospholipid, apoA-I, and possibly apoA-IV into HDL. Chylomicron phospholipid appears to give rise to vesicles which are probably incorporated into preexisting HDL. Chylomicron surface components may be an important source of plasma HDL.

Human apolipoprotein A-IV. Intestinal origin and distribution in plasma.

The role of the human intestine has been explored as a site of synthesis of apoA-IV, a major apoprotein of human intestinal triglyceride-rich lipoproteins. Intestinal biopsies were performed on normal volunteers while fasting and after lipid ingestion. Indirect immunofluorescence demonstrated a marked increase in immunofluorescence for apoA-IV during lipid absorption consistent with an increased intracellular content. ApoA-IV comprised 10-13% of chylomicron apoprotein and 24-30% of intestinal very low density lipoprotein (VLDL) as assessed by densitometry of sodium dodecyl sulfate gels of lipoproteins from chylous urine (mesenteric lymphatic-urinary fistula) and thoracic duct lymph (postoperative fistula). After one subject with chyluria ingested 40 g of corn oil, triglyceride excretion in urine was accompanied by an increased excretion of apoA-IV. 11.5 g of triglyceride and 81 mg of apoA-IV were recovered in the urine. In chylous urine 56% of apoA-IV was in the triglyceride-rich lipoproteins (chylomicrons and intestinal VLDL) and 44% in the d > 1.006-g/ml fraction. Normal plasma apoA-IV was 15.7+/-0.9 mg/dl (n = 14) whereas four subjects with abetalipoproteinemia had reduced levels 1.2, 7.6, 9.6, and 8.3 mg/dl, respectively. Lipid feeding in normal volunteers resulted in a rise in plasma apoA-IV (16.1+/-0.7 mg/dl to 18.5+/-0.7 mg/dl, n = 5, P < 0.01). In fasting plasma, 98% of apoA-IV was in the d > 1.21-g/ml fraction. In lipemic plasma, 10% of apoA-IV was associated with triglyceride-rich lipoproteins and 90% with the d > 1.21-g/ml fraction. Agarose column chromatography of fasting plasma confirmed that the bulk of plasma apoA-IV is free, unassociated with lipoproteins. These results demonstrate that apoA-IV is present in human intestinal epithelial cells and is secreted as a chylomicron and VLDL apoprotein. Within fasting plasma most of the apoA-IV is found free, unassociated with lipoproteins. After lipid ingestion apoA-IV is also found in plasma chylomicrons indicating that some apoA-IV remains associated with chylomicrons in plasma during chylomicron metabolism, although some may be transferred from the chylomicron surface.

Human intestinal lipoproteins. Studies in chyluric subjects.

To explore the role of the human intestine as a source of apolipoproteins, we have studied intestinal lipoproteins and apoprotein secretion in two subjects with chyluria (mesenteric lymphatic-urinary fistulae). After oral corn oil, apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) output in urine increased in parallel to urinary triglyceride. One subject, on two occasions, after 40 g of corn oil, excreted 8.4 and 8.6 g of triglyceride together with 196 and 199 mg apoA-I and on one occasion, 56 mg apoA-II. The other subject, after 40 g corn oil, excreted 0.3 g triglyceride and 17.5 mg apoA-I, and, after 100 g of corn oil, excreted 44.8 mg apoA-I and 5.8 mg apoA-II. 14.5+/-2.1% of apoA-I and 17.7+/-4.3% of apoA-II in chylous urine was in the d < 1.006 fraction (chylomicrons and very low density lipoprotein). Calculations based on the amount of apoA-I and apoA-II excreted on triglyceride-rich lipoproteins revealed that for these lipid loads, intestinal secretion could account for 50 and 33% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Similarly, subject 2 excreted 48-70% and 14% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Chylous urine contained chylomicrons, very low density lipoproteins and high density lipoproteins, all of which contained apoA-I. Chylomicrons and very low density lipoproteins contained a previously unreported human apoprotein of 46,000 mol wt. We have called this apoprotein apoA-IV because of the similarity of its molecular weight and amino acid composition to rat apoA-IV. In sodium dodecyl sulfate gels, chylomicron apoproteins consisted of apoB 3.4+/-0.7%, apoA-IV 10.0+/-3.3%, apoE 4.4+/-0.3%, apoA-I 15.0+/-1.8%, and apoC and apoA-II 43.3+/-11.3%. Very low density lipoprotein contained more apoB and apoA-IV and less apoC than chylomicrons. Ouchterlony immunodiffusion of chylomicron apoproteins revealed the presence of apoC-I, apoC-II, and apoC-III. In contrast, plasma chylomicrons isolated during a nonchyluric phase revealed a markedly altered chylomicron apoprotein pattern when compared with urinary chylomicrons. The major apoproteins in plasma chylomicrons were apoB, apoE, and the C peptides: no apoA-I or apoA-IV were present in sodium dodecyl sulfate gels indicating that major changes in chylomicron apoproteins occur during chylomicron metabolism. When incubated in vitro with plasma, urinary chylomicrons lost apoA-I and apoA-IV and gained apoE and apoC. Loss of apoA-I and apoA-IV was dependent upon the concentration of high density lipoproteins in the incubation mixture. These studies demonstrate that the human intestine secretes significant amounts of apoA-I and apoA-II during lipid absorption. Subsequent transfer of apoproteins from triglyceride-rich lipoproteins to other plasma lipoproteins may represent a mechanism whereby the intestine contributes to plasma apoprotein levels.

Effect of biliary diversion on rat mesenteric lymph apolipoprotein-I and high density lipoprotein.

The effect of biliary diversion on intestinal apolipoprotein (apoA)-I and high density lipoprotein formation was studied in mesenteric lymph fistula rats. Bile diversion was produced by an exteriorized catheter that allowed interruption and reconstitution of the enterohepatic circulation. Bile diversion reduced lymph cholesterol output from 0.47+/-0.05 mumol/h to 0.17+/-0.03 mumol/h (P < 0.025), and lymph triglyceride output from 3.6+/-0.3mumol/h to 0.6+/-0.05 mumol/h (P < 0.025) after 24 h. This was due to depletion of lymph chylomicrons and very low density lipoprotein (VLDL). Despite the reduced lipid outputs, lymph apoA-I output was maintained during biliary diversion (basal: 119+/-15 mug/h; diverted 140+/-20 mug/h, n = 12). During biliary diversion, high density lipoprotein (HDL) were maintained in mesenteric lymph as shown by lipoprotein and immunoelectrophoresis. Bile diversion altered the lipid composition of lymph HDL. Bile-diverted lymph HDL was depleted in total cholesterol and has a greater phospholipid/cholesterol ester ratio than basal lymph HDL. Lymph HDL contained discoidal particles when examined by negative stain electron microscopy. Bile diversion was associated with a reduction in the size of discoidal HDL particles (basal, nondiverted, 165+/-7A (n = 112) compared with diverted 126+/-5A (n = 98, P < 0.025). Experiments were then carried out to determine the source of the apoA-I and HDL found in lymph from bile-diverted animals. The transfer of HDL from plasma into lymph was determined by the intravenous infusion of (125)I-apoA-I labeled HDL into lymph fistula rats. In both nonbile-diverted and diverted rats, the specific activity of apoA-I in the HDL fraction of lymph was 23% of the specific activity of apoA-I in plasma HDL, indicating that the major portion (75%) of mesenteric lymph apoA-I did not come from plasma filtration. In other experiments the intraduodenal infusion of [(3)H]leucine to bile fistula, lymph fistula rats resulted in relative fivefold increase in the specific activity in apoA-I in lymph HDL when compared with the specific activity of apoA-I in plasma HDL from the same animal. We conclude that intestinal apoA-I secretion is maintained during biliary diversion and that synthesis of this apoprotein occurs in the absence of chylomicron formation. We also conclude that discoidal HDL are present in mesenteric lymph despite reduced triglyceride absorption and secretion into lymph.

Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease.

BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten-free diet.

BACKGROUND: Duodenal injury persists in some coeliac disease patients despite gluten-free diet, and is associated with adverse outcomes. AIM: To determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients. METHODS: A nested cross-sectional analysis was performed on coeliac disease patients with self-reported moderate or severe symptoms while following a gluten-free diet, who underwent protocol-mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy. RESULTS: Of 1345 symptomatic patients, 511 (38%, 95% CI, 35-41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18-29 years, 95% CI, 2.5-10.4) was a risk factor while longer duration on gluten-free diet was protective (OR, 0.37, 95% CI, 0.24-0.55 for 4-5.9 vs. 1-1.9 years). Villus atrophy was associated with use of proton-pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1-2.3), non-steroidal anti-inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2-2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2-2.5). Symptoms were not associated with villus atrophy after adjusting for covariates. Conclusions A majority of symptomatic coeliac disease patients did not have active disease on follow-up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry.

BACKGROUND: Refractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome. AIM: To create a prognostic model to estimate survival of patients with refractory coeliac disease. METHODS: We evaluated predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5-year mortality. RESULTS: The multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11-63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5-year follow-up (cumulative 5-year all-cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5-year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38-3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22-6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61-0.85). A simple weighted three-factor risk score was created to estimate 5-year survival. CONCLUSIONS: Using data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5-year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow-up.

The coeliac stomach: gastritis in patients with coeliac disease.

BACKGROUND: Lymphocytic gastritis (LG) is an uncommon entity with varying symptoms and endoscopic appearances. This condition, as well as two forms of H. pylori-negative gastritis [chronic active gastritis (CAG) and chronic inactive gastritis (CIG)], appears to be more common in patients with coeliac disease (CD) based on single-centred studies. AIM: To compare the prevalence of LG, CAG and CIG among those with normal duodenal histology (or nonspecific duodenitis) and those with CD, as defined by villous atrophy (Marsh 3). METHODS: We analysed all concurrent gastric and duodenal biopsy specimens submitted to a national pathology laboratory during a 6-year period. We performed multiple logistic regression to identify independent predictors of each gastritis subtype. RESULTS: Among patients who underwent concurrent gastric and duodenal biopsy (n = 287,503), the mean age was 52 and the majority (67%) were female. Compared to patients with normal duodenal histology, LG was more common in partial villous atrophy (OR: 37.66; 95% CI: 30.16-47.03), and subtotal/total villous atrophy (OR: 78.57; 95% CI: 65.37-94.44). CD was also more common in CAG (OR for partial villous atrophy 1.93; 95% CI: 1.49-2.51, OR for subtotal/total villous atrophy 2.42; 95% CI: 1.90-3.09) and was similarly associated with CIG (OR for partial villous atrophy 2.04; 95% CI: 1.76-2.35, OR for subtotal/total villous atrophy 2.96; 95% CI: 2.60-3.38). CONCLUSIONS: Lymphocytic gastritis is strongly associated with coeliac disease, with increasing prevalence correlating with more advanced villous atrophy. Chronic active gastritis and chronic inactive gastritis are also significantly associated with coeliac disease. Future research should measure the natural history of these conditions after treatment with a gluten-free diet.