Ileal function in patients with untreated adult coeliac disease.

A double-lumen perfusion technique has been used to investigate jejunal and ileal absorption of glucose, water, and electrolytes in a group of patients with untreated adult coeliac disease. Correct positioning of the tube was confirmed by measuring the differential jejunal and ileal handling of bicarbonate. Eight control subjects and eight patients with coeliac disease were perfused with an isotonic electrolyte solution containing 50 mM glucose and 25 mM bicarbonate. The group of coeliac patients had impaired jejunal absorption of glucose (P less than 0.001), water (P less than 0.01), sodium (P less than 0.02), and chloride (P greater than 0.05) compared with the control group. In contrast the group of coeliac patients had normal ileal glucose and water absorption and increased ileal sodium (P greater than 0.01) and chloride (P greater than 0.05) absorption compared with the controls. Evidence for ileal adaptation was found in three individual patients who had absorptive values outside 2SD of the normal mean. The results indicate that the distal small intestine in coeliac disease has the ability to adopt to the damage and loss of absorptive capacity in the proximal small intestine.     

Faecal calprotectin concentrations in untreated coeliac patients

OBJECTIVE: Calprotectin is a granulocyte cytosolic protein that is considered to be a promising marker of subclinical inflammation. High faecal calprotectin concentrations (FCCs) have been found in several intestinal diseases, but no data are currently available on patients with coeliac disease. The purpose of this pilot study was to evaluate FCCs in untreated coeliac patients and to correlate them with clinical score and histological characteristics. MATERIAL AND METHODS: Twenty-eight consecutive coeliac patients were recruited. Thirty healthy adult volunteers participated as the control group. FCCs were determined by ELISA. Clinical assessment was carried out in all patients. The histological severity of lesions and the infiltration of neutrophil polymorphs in the intestinal mucosa were also evaluated. Mean FCCs in patients and the control group were compared by means of the t-test for independent samples. In coeliac patients, differences in FCCs in subgroups identified by clinical score, lesion severity and neutrophil infiltration were evaluated by the Kruskal-Wallis non-parametric test. RESULTS: FCCs in untreated coeliac patients were not significantly different from those in controls (p=0.163). Among coeliac patients, FCCs were not significantly different in relation to the level of clinical score, lesion severity or neutrophil infiltration (p=0.92, p=0.96 and p=0.74, respectively). CONCLUSIONS: This study shows, for the first time, that FCCs in untreated coeliac patients do not differ significantly from those in controls.     

Faecal calprotectin concentrations in untreated coeliac patients

Objective. Calprotectin is a granulocyte cytosolic protein that is considered to be a promising marker of subclinical inflammation. High faecal calprotectin concentrations (FCCs) have been found in several intestinal diseases, but no data are currently available on patients with coeliac disease. The purpose of this pilot study was to evaluate FCCs in untreated coeliac patients and to correlate them with clinical score and histological characteristics. Material and methods. Twenty-eight consecutive coeliac patients were recruited. Thirty healthy adult volunteers participated as the control group. FCCs were determined by ELISA. Clinical assessment was carried out in all patients. The histological severity of lesions and the infiltration of neutrophil polymorphs in the intestinal mucosa were also evaluated. Mean FCCs in patients and the control group were compared by means of the t-test for independent samples. In coeliac patients, differences in FCCs in subgroups identified by clinical score, lesion severity and neutrophil infiltration were evaluated by the Kruskal-Wallis non-parametric test. Results. FCCs in untreated coeliac patients were not significantly different from those in controls (p=0.163). Among coeliac patients, FCCs were not significantly different in relation to the level of clinical score, lesion severity or neutrophil infiltration (p=0.92, p=0.96 and p=0.74, respectively). Conclusions. This study shows, for the first time, that FCCs in untreated coeliac patients do not differ significantly from those in controls.     

Assessment of autonomic function in untreated adult coeliac disease

AIM: Some recent studies showed that alteration of upper-gut motility in coeliac disease may be related to dysfunction of autonomic nervous system. The aim of our study was to investigate whether autonomic nervous system was altered in untreated and unselected coeliac disease patients. METHODS: We studied 8 untreated and consecutive coeliac disease patients (2 males and 6 females, age range 37+/-14.5 years). Histological evaluation of duodenal mucosa, anti-gliadin antibodies (AGA), antiendomysial antibodies (EMA) and anti-tTG antibodies and sorbitol H2 breath test were performed in all patients. Extrinsic autonomic neuropathy was assessed by the standardized measurement of cardiovascular reflexes (lying-to-standing, Valsalva manoeuvre, deep breathing, sustained handgrip). The results obtained were compared with a healthy, asymptomatic control group (6 males and 7 females, age range 42.3+/-13.5 years). RESULTS: Coeliac patients exhibited a lower increase of PAS as a response to isometric effort, a reduction of spectral power LF as a response to clinostatic position, but without statistical significance. Also they showed a lower tolerance to orthostatic position, associated with a latent disequilibrium of sympathetic-vagal balance, a relative prevalence of parasympathetic component of the autonomic function. However, these results were not statistically significant when compared with control group (P = n.s.). And they were unchanged after 6 and 12 mo of gluten-free diet. CONCLUSION: This study failed to confirm a significant correlation between autonomic dysfunction and coeliac disease, yet we could not exclude a role of autonomic dysfunction in the genesis of systemic symptoms in some coeliacs.     

Levels of salivary IgA in treated and untreated coeliac disease

Estimations of the concentration of secretory IgA have been performed on 152 specimens of saliva from 46 patients with adult coeliac disease. The results are compared with values observed in 20 normal subjects. The mean salivary IgA concentration was 9 mg% in 36 patients on a normal diet and 7.9 mg% in 21 patients on a gluten-free diet. In 20 normals the mean salivary IgA was 7.1 mg%. Nine patients were studied before and after gluten exclusion. Seven of these showed a marked fall in salivary IgA concentration after gluten was excluded.     

T cell depletion in untreated adult coeliac disease.

The proportional and absolute numbers of circulating thymus dependent lymphocytes (T cells) were reduced in untreated patients with coeliac disease but were normal after treatment with a gluten free diet. There was an inverse correlation between circulating T cell numbers and jejunal intraepithelial lymphocytes. This evidence suggests a possible role for T cells in the pathogenesis of coeliac disease and is a further example of disturbed cell mediated immunity in this condition.     

Electrogenic glucose absorption in untreated and treated coeliac disease.

Using a method for measuring changes in transmural potential difference across the human jejunum in vivo, the operational kinetic parameters of 'Apparent Km' and PD max for the active electrogenic component of glucose absorption were estimated in a group of healthy volunteers and in patients with coeliac disease. Both the 'Apparent Km' (17+/2mM; mean +/SEM) and the PD max (8.6+/0.7 mV) in nine patients with untreated coeliac disease were significantly lower (p less than 0.005) than in the control group ('Apparent Km' = 74+/5mM; PD max 12.8+/0.9mV, n=20). Treatment of five coeliac patients by gluten withdrawal for less than three months increased significantly the values of both the "Apparent Km (35+/6mM) and the TPD max (11.4+/1.2mV). Treatment of five patients for more than six months caused a further increase in the values of both kinetic parameters ('Apparent Km' = 108+/13mM; PD max =15.6+/2.7mV) to levels which exceeded those in healthy subjects. The possible interpretations of the differences in the kinetic characteristics of electrogenic glucose transport between coeliac patients and healthy subjects are discussed.     

Osteoporosis in treated adult coeliac disease.

Forty five women and 10 men with coeliac disease diagnosed in adult life, who were already on a gluten free diet, had serial bone mineral density measurements at the lumbar spine and femoral neck over 12 months. Osteoporosis, defined as a bone mineral density (BMD) < or = 2 SD below the normal peak bone mass was found in 50% of male and 47% of female coeliac patients. Patients with a BMD < or = 2 SD below age and sex matched normal subjects, had a significantly lower body mass index (21.3 kg.m-2 compared with 25.2 kg.m-2, p < 0.02 Wilcoxon rank sum test) and lower average daily calcium intake (860 mg/day compared with 1054 mg/day, p < 0.05 Wilcoxon rank sum test) than patients with normal bone mineral density. In postmenopausal women with coeliac disease there was a strong correlation between the age at menopause and BMD at both the lumbar spine (r = 0.681, p < 0.01, Spearman's rank correlation) and femoral neck (r = 0.632, p < 0.01). No overall loss of bone was shown over the 12 months of follow up, and relative to the reference population there was a significant improvement in BMD at the lumbar spine in women (p < 0.025, paired t test) and at the femoral neck in men (p < 0.05, paired t test). There was a significant negative correlation between the annual percentage change in BMD at the lumbar spine and the duration of gluten free diet (r = -0.429, p<0.01, Spearman's rank correlation), with the largest gain in BMD in patients with most recently diagnosed coeliac disease. Osteoporosis was shown in 47% of patients with treated adult coeliac disease. Recognised risk factors for osteoporosis in the general population including low body mass index, dietary calcium intake, and early menopause are particularly important in coeliac disease. Treatment of coeliac disease with a gluten free diet probably protects against further bone loss, and in the early stages is associated with a gain in bone mineral density.     

Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists

We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.     

Increased concanavalin A induced suppression in treated and untreated coeliac disease.

The generation of suppression by concanavalin A in peripheral blood mononuclear cells in treated and untreated coeliac subjects using an in vitro assay was found to be significantly increased when compared with controls. The response of peripheral blood mononuclear cells to the plant mitogen concanavalin A (con A) was also significantly depressed in both groups of coeliac patients. It is proposed that the depressed cell mediated immunity found in this and other studies in coeliac patients is because of increased suppression. The possible connection between these findings and the increased incidence of malignancy also found in coeliac disease is discussed.     

Raised number of jejunal IgG2-producing cells in untreated adult coeliac disease compared with food allergy

The subclass distribution of IgG-producing immunocytes was studied by two colour immunohistochemistry with monoclonal antibodies in jejunal biopsy specimens from 10 adults with untreated coeliac disease, 11 coeliac disease patients on a gluten free diet, and seven patients with established food allergy. Paired immunofluorescence staining was performed with subclass specific murine monoclonal antibodies in combination with polyclonal rabbit antibody reagent to total IgG; the proportion of cells belonging to each subclass could thereby be determined. The ratio of IgG2 immunocytes was significantly higher (p less than 0.05) in untreated coeliac disease patients (median, 35.2%; range, 26.7-65.2%) than in those on a gluten free diet (median, 7.3%; range, 0-31.9%) or those having food allergy (median, 12.5%; range, 0-36.5%). The disparity in the local IgG2 response between patients with untreated coeliac disease and those with food allergy might be due to differences in the nature of the antigenic stimuli, dissimilar genetic 'make-up' of the subjects, or both.     

Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease

INTRODUCTION: Untreated coeliac disease may induce malabsorption of many nutrients. It may also induce vitamin K deficiency, which causes prolongation of the prothrombin time. The aim of the present study was to evaluate the prevalence and associations of prolonged prothrombin time in a series of coeliac adults. METHODS: We carried out a cross-sectional analysis of data collected on 390 adults with untreated coeliac disease diagnosed from January 1997 to December 2000. Prolonged prothrombin time was defined as INR > or = 1.4. RESULTS: A prolonged prothrombin time was found in 72 coeliac patients (18.5%). Parenteral vitamin K therapy was required in 5.6% of patients. Patients with prolonged prothrombin time had significant lower values of haemoglobin, iron, proteins, cholesterol and serum aspartate transaminase, and significantly higher prevalence of diarrhoea, weight loss, abdominal pain and low bone mineral density in comparison with patients with normal prothrombin time. However, low bone density was present in 11.6% of patients with normal INR. A prolonged prothrombin time was only found in a few patients with subclinical coeliac disease (0.9%). CONCLUSIONS: Data indicate that the prevalence of prolonged prothrombin time is about 20% in a large series of adult untreated coeliac patients. A prolonged prothrombin time was significantly related to all the markers of severe malabsorption, including low mineral density. Our suggestion is that vitamin K related proteins may also play a role in determining or worsening calcium homeostasis disorders in coeliac disease. The very low prevalence of coagulation disorders in subclinical coeliac disease indicates that there is no need to screen for coeliac disease in patients with isolated coagulation disorders.     

Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus. The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). Metformin has been reported to inhibit DPP-4. Here we investigated the acute effects of metformin and GLP-1 alone or in combination on plasma DPP-4 activity, active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus. Ten subjects with type 2 diabetes mellitus (8 male and 2 female; age, 68.7 ± 2.6 years [mean ± SEM]; body mass index, 29.6 ± 1.7 kg/m²; hemoglobin A_1c, 7.0% ± 0.1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design: metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1.5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP-1(Metformin + GLP-1). At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose; and responses were assessed over the next 3 hours. This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined. Mean area under curve (AUC) _{0-180 minutes} plasma glucose responses were lowest after Metformin + GLP-1 (mean ± SEM, 1629 ± 90 mmol/[L min]) compared with GLP-1 (1885 ± 86 mmol/[L min], P < .002) and Metformin (2045 ± 115 mmol/[L min], P < .001). Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 ± 498 mU/[L min]) or GLP-1 (5655 ± 854 mU/[L min]) treatment, and both were higher than Metformin (3521 ± 410 mU/[L min]; P < .001 and P < .05, respectively). Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 ± 2 μmol/[mL min], P < .001) and Metformin (1508 ± 2 μmol/[mL min], P < .002) compared with GLP-1 (1587 ± 3 μmol/[mL min]). Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 × 10⁴ ± 51 × 10⁴ pmol/[L min]) compared with GLP-1 (484 × 10⁴ ± 31 × 10⁴ pmol/[L min], P < .001) and Metformin (419 × 10⁴ ± 34 × 10⁴ pmol/[L min], P < .001), respectively. In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection. In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar. Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency.     

Enterokinase in normal intestinal biopsies and those from patients with untreated coeliac disease

Enterokinase was measured in peroral intestinal biopsies showing normal histology and in those from untreated coeliac patients which showed gross villous atrophy. There was no significant difference in the specific activity of enterokinase between these two groups. These results do not support the recent hypothesis that enterokinase is a brush border enzyme, but would be consistent with the idea that it is adsorbed to the cell membrane following secretion.     

Body composition and calcium metabolism in adult treated coeliac disease.

Twenty two treated adult patients with coeliac disease (aged 20-70 years) were examined. Body composition was assessed from anthropometry and directly measured by dual photon absorptiometry. Bone mineral content was measured in the spine (dual photon absorptiometry) and at two forearm sites (single photon absorptiometry). Compared with age matched healthy subjects, treated coeliac patients had lower body mass index (-5%, p less than 0.05) and lower directly measured total body fat mass (-30%, p less than 0.001). They also had decreased bone mineral content (-9 to -13%, p less than 0.01) in the spine and in the forearms. The serum concentrations of albumin, D vitamin binding protein, and iron were reduced (-6 to -22%, p less than 0.01), but otherwise blood and urine analyses were normal. We conclude that this group of treated adult coeliac patients had a reduced fat mass and bone mineral content compared with the general population.     

Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2

The glucagon-like peptides (glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)) are released from enteroendocrine cells in response to nutrient ingestion. GLP-1 enhances glucose-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying and feeding. GLP-1 also has proliferative, neogenic and antiapoptotic effects on pancreatic beta-cells. More recent studies illustrate a potential protective role for GLP-1 in the cardiovascular and central nervous systems. GLP-2 is an intestinal trophic peptide that stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment. GLP-2 also regulates intestinal glucose transport, food intake and gastric acid secretion and emptying, and improves intestinal barrier function. Thus, GLP-1 and GLP-2 exhibit a diverse array of metabolic, proliferative and cytoprotective actions with important clinical implications for the treatment of diabetes and gastrointestinal disease, respectively. This review will highlight our current understanding of the biology of GLP-1 and GLP-2, with an emphasis on both well-characterized and more novel therapeutic applications of these peptides.     

High frequency of coeliac disease in adult patients with type-I diabetes

Anti-reticulin antibodies were measured by an indirect immunofluorescence method in 195 consecutive patients with insulin-dependent diabetes mellitus, and positive titres were found in 8 patients. A jejunal biopsy was performed in these patients, all of whom had small-intestinal atrophy. Thus the frequency of coeliac disease in adult diabetes patients was 4.1%. The patients had no signs of malabsorption or of significant abdominal complaints. We conclude that coeliac disease is commoner in type-I diabetes than in the normal population, and measurement of anti-reticulin antibodies seems to be a suitable screening method.