Roberto M. Mazure

Risk of fractures in celiac disease patients: a cross-sectional, case-control study

OBJECTIVES:Although osteopenia and osteoporosis are well-recognized complications of celiac disease, no controlled studies have been done to assess the prevalence of fractures in a large cohort of patients. The objectives of this study were to determine the prevalence of bone fractures and vertebral deformities in celiacs and to analyze the relationship between fractures and clinical data of patients.METHODS:We studied 165 patients with a well-established diagnosis of celiac disease. A similar number of age- and gender-matched control subjects with functional GI disorders were evaluated. The design of the study was cross-sectional, with a retrospective historical review through a personal interview of all subjects. All patients underwent bone mineral density measurement by dual-energy, x-ray absorptiometry and spinal x-ray. Vertebral deformities were determined by visual inspection of spinal x-rays and by morphometric analysis.RESULTS:Among celiacs, 41 patients (25%) referred have had from one to five fractures in the peripheral skeleton. On the contrary, only 14 (8%) control subjects experienced fractures. This difference was highly significant (odds ratio, 3.5; 95% confidence interval [CI], 1.8–7.2; p < 0.0001). Although inspection of spinal x-rays showed evidence of vertebral deformities in the lumbar spine in only two patients, a more detailed examination of lateral x-rays using morphometric criteria detected lumbar spine vertebral deformities in nine (five also had fractures in the peripheral skeleton) and in four controls (odds ratio, 2.8; 95% CI, 0.7–11.5; p = NS). Eighty percent of fractures were detected before the diagnosis of celiac disease or in patients who were noncompliant with the gluten-free diet; only 7% of patients experienced fractures after starting treatment. Regression analysis adjusted for multiple comparisons showed that patients with fractures were diagnosed with celiac disease later (p < 0.06) and remained undiagnosed for more prolonged periods (p < 0.05). There was a trend, which did not reach statistical significance, for a lower bone mineral density in the lumbar spine and total skeleton among patients with fractures.CONCLUSIONS:This study has demonstrated that patients with celiac disease had a high prevalence of bone fractures in the peripheral skeleton. Most of these events occurred before diagnosis or while patients were noncompliant with gluten-containing diet. Our results suggest that early diagnosis and effective treatment of celiac disease were the most relevant measures to protect patients from the risk of fractures.

Pre- and post-treatment serum levels of cytokines IL-1β, IL-6, and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia?

Objective:Decreased bone mineral density is a common finding in untreated celiac disease patients. However, the precise pathophysiology of osteopenia remains incompletely understood. Pathological features of gluten sensitivity are associated with local release of proinflammatory and antiinflammatory cytokines. We investigated the serum levels of IL-1β, IL-6, and IL-1 receptor antagonist in celiac patients and correlated them with bone density measurements.Methods:We assessed serum samples of 16 female patients at the time of diagnosis (on an unrestricted diet) and after a mean time of 37 months on a gluten-free diet. At the same time, bone mineral density in the lumbar spine and total skeleton was determined by DEXA.Results:Untreated patients had high serum levels of IL-1β and IL-6 and normal IL-1-RA. Treatment produced a decrease in median IL-1β levels (p = NS) and a significant diminution of IL-6 (p < 0.05). On the contrary, IL-1-RA increased significantly after treatment (p < 0.05). Baseline lumbar spine Z-score and IL-6 levels exhibited a significant inverse correlation (r =–0.61; p < 0.01). Patients with more severe baseline osteopenia (< -2 Z-scores) had a significantly lower IL-1-RA than those with less bone compromise (> -2 Z-scores).Conclusions:Our data demonstrate that the inflammatory process observed in active celiac disease is associated with high serum levels of IL-1β and IL-6 and normal levels of IL-1-RA. Treatment significantly reduces both proinflammatory cytokines and significantly increases the antiinflammatory one. We also suggest that these cytokines might have a role in the osteopenia associated with celiac disease.

Body composition and bone mineral density in untreated and treated patients with celiac disease

Body composition and bone mineral density (BMD) were studied by X-ray absorptiometry in 20 untreated and 12 treated women with celiac disease, as well as in 85 age-matched control women. Untreated patients had a significantly lower body weight, fat mass, lean tissue mass and BMD at the lumbar spine and total skeleton compared to controls (p < 0.001 for all parameters). Treated patients had also a significantly lower body weight (p < 0.01) fat mass (p < 0.05) and bone mineral density at lumbar spine and total skeleton (p < 0.05) compared with controls, but lean tissue mass was not diminished. However, treated patients had a significantly higher body weight, fat mass and BMD of the total skeleton compared with untreated celiac patients (p < 0.01 for all parameters). Serum alkaline phosphatase levels were increased in untreated patients but serum 250HD was normal. In conclusion, celiac disease causes a global and almost universal reduction of fat mass and BMD. The results of this cross-sectional study suggest that osteopenia does not seem to be completely restored by adequate treatment. Alteration of vitamin D metabolism was not the cause of osteopenia in the majority of patients.

Gynaecological and obstetric disorders in coeliac disease: frequent clinical onset during pregnancy or the puerperium.

Background and aim While gynaecological and obstetric disorders have been reported among women with coeliac sprue, their true prevalence and relationship to the coeliac disease process has not been completely elucidated. Our aims were to determine: (1) the prevalence of gynaecological and obstetric problems in patients with coeliac disease and the influence of strict gluten restriction on their occurrence, (2) the effect of pregnancy on the clinical course of coeliac disease and (3) the clinical features of those patients with onset of coeliac disease during pregnancy and the puerperium. Patients and methods The gynaecological and obstetric history of 130 coeliac patients and 130 age-matched healthy female controls were compared in a case-control study. Results In comparison to the controls, untreated coeliac disease patients exhibited significantly later menarche, an earlier menopause, an increased prevalence of secondary amenorrhoea and a greater incidence of spontaneous abortions. Patients who had adhered, in the long term, to a gluten-free diet had gynaecological and obstetric history indistinguishable from controls. Clinical deterioration of coeliac disease was observed in untreated patients during 17% of their pregnancies. In 14% of those untreated patients who were pregnant symptoms related to coeliac disease were manifested for the first time during either pregnancy (n = 7) or the puerperium (n = 4). Nine of these patients had underestimated features suggestive of coeliac disease. Conclusion The early diagnosis and treatment of coeliac disease may avoid significant gynaecological and obstetric complications in affected women. Celiac sprue must always be borne in mind among patients who develop diarrhoea and weight loss during pregnancy and/or the puerperium.

Dynamics of celiac disease-specific serology after initiation of a gluten-free diet and use in the assessment of compliance with treatment.

BACKGROUND The usefulness of celiac disease-related serology in monitoring patients on a gluten-free diet has been debated. AIM To describe serologic changes over time and assess whether serology tests can predict compliance with the gluten-free diet. METHODS Sera obtained at baseline and every 3 months thereafter for 1 year in 82 adult celiac disease patients were assayed for: (1) IgA antigliadin, (2) IgA anti-tissue transglutaminase, (3) IgA endomysial, (4) IgA, and (5) IgG anti-deamidated gliadin peptides, (6) dual detection of IgA and IgG anti-deamidated gliadin peptides, (7) a single assay for IgA and IgG of both anti-deamidated gliadin peptide and anti-tissue transglutaminase, and (8) IgA antiactin antibodies. RESULTS At 3 months after diagnosis, most antibody assays significant decrease in mean concentrations (p<0.0001) and the percentage of positive samples (p<0.0001) with further improvement in subsequent determinations. Strictly adherents had significantly lower concentrations of antibodies (p<0.01 to p<0.00001) and smaller proportion of positive samples for IgA endomysial, IgA antiactin antibodies and IgA antigliadin (15.6%, 17.4% and 23.9%, respectively) than partially compliant. At 1 year, IgA endomysial (p<0.02), IgA antiactin antibodies (p<0.05) and anti-tissue transglutaminase (p<0.02) predicted the degree of compliance. CONCLUSIONS Gluten-free diet treatment produced rapid and significant qualitative and quantitative changes in celiac disease-related antibodies which may be useful for monitoring dietary compliance.

Permeability, zonulin production, and enteropathy in dermatitis herpetiformis

BACKGROUND & AIMS Dermatitis herpetiformis (DH) is characterized by variable degrees of enteropathy and increased intestinal permeability. Zonulin, a regulator of tight junctions, seems to play a key role in the altered intestinal permeability that characterizes the early phase of celiac disease. Our aim was to assess both intestinal permeability and serum zonulin levels in a group of patients with DH having variable grades of enteropathy. METHODS We studied 18 DH patients diagnosed on the basis of characteristic immunoglobulin (Ig)A granular deposits in the dermal papillae of noninvolved skin. Results were compared with those of classic celiac patients, patients with linear IgA dermatosis, and healthy controls. RESULTS According to Marshs classification, 5 patients had no evidence of enteropathy (type 0), 4 patients had type II, 2 patients had type IIIb damage, and 7 patients had a more severe lesion (type IIIc). Intestinal permeability (lactulose/mannitol ratio [lac/man]) was abnormal in all patients with DH. Patients with more severe enteropathy had significantly greater permeability ( P < .05). The serum zonulin concentration (enzyme-linked immunosorbent assay) for patients with DH was 2.1 +/- .3 ng/mg with 14 of 16 (87.5%) patients having abnormally increased values. In contrast, patients with linear IgA dermatosis had normal histology, normal intestinal permeability, and negative celiac serology. CONCLUSIONS Increased intestinal permeability and zonulin up-regulation are common and concomitant findings among patients with DH, likely involved in pathogenesis. Increased permeability can be observed even in patients with no evidence of histologic damage in biopsy specimens. Patients with linear IgA dermatosis appear to be a distinct population with no evidence of gluten sensitivity.

Successful treatment of retractile mesenteritis with oral progesterone

Retractile mesenteritis is a rare inflammatory mesenteric disorder that involves the intestine secondarily. The natural history of this process is diverse, but most patients require some empiric therapeutic measures. Up to now, pharmacological therapy has included corticosteroids, colchicine, and immunosuppressive drugs. Although these drugs are successful in most patients, some have been refractory to these therapies and, in others, the beneficial effects were counterbalanced by adverse reactions. Many patients require surgery, but most have poor results. This report describes a 42-year-old man with histologically proven retractile mesenteritis refractory to surgical intervention who had a good response to oral progesterone (10 mg/day for 6 months) with complete disappearance of tumor mass and clinical symptoms. No adverse effects were detected. Current knowledge about the mechanism by which progesterone affects fibrogenesis is scanty. It seems likely that progesterone down-regulates proliferation and metabolism of fibroblasts and fibrogenesis.

Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease.

Background/Aims: The aim of this exploratory trial was to establish if the probiotic Bifidobacterium natren life start (NLS) strain strain may affect the clinical course and pathophysiological features of patients with untreated celiac disease (CD). Positive findings would be helpful in directing future studies. Methods: Twenty-two adult patients having 2 positives CD-specific tests were enrolled. Patients were randomized to receive 2 capsules before meals for 3 weeks of either Bifidobacterium infantis natren life start strain super strain (Lifestart 2) (2×109 colony-forming units per capsule) (n=12) or placebo (n=10), whereas they also consumed at least 12 g of gluten/day. A biopsy at the end of the trial confirmed CD in all cases. The primary outcome was intestinal permeability changes. Secondary endpoints were changes in symptoms and the Gastrointestinal Symptom Rating Scale, and in immunologic indicators of inflammation. Results: The abnormal baseline intestinal permeability was not significantly affected by either treatment. In contrast to patients on placebo, those randomized to B. infantis experienced a significant improvement in Gastrointestinal Symptom Rating Scale (P=0.0035 for indigestion; P=0.0483 for constipation; P=0.0586 for reflux). Final/baseline IgA tTG and IgA DGP antibody concentration ratios were lower in the B. infantis arm (P=0.055 for IgA tTG and P=0.181 for IgA DGP). Final serum macrophage inflammatory protein-1&bgr; increased significantly (P<0.04) only in patients receiving B. infantis. The administration of B. infantis was safe. Conclusions: The study suggests that B. infantis may alleviate symptoms in untreated CD. The probiotic produced some immunologic changes but did not modify abnormal intestinal permeability. Further studies are necessary to confirm and/or expand these observations.

Is it necessary to screen for celiac disease in postmenopausal osteoporotic women

Decreased bone mass is a frequent finding in celiac patients, and subclinical celiac disease (CD) appears to be unusually overrepresented among patients with idiopathic osteoporosis. Since silent CD may be more common than previously believed, it has been suggested that all osteoporotic patients should be checked for occult CD. The aim of this study was to explore the prevalence of CD in a well-defined population of postmenopausal osteoporotic women. We evaluated 127 consecutive postmenopausal patients (mean age: 68 years; range: 50-82 years) with verified osteoporosis. The observed prevalence of CD in this group was compared to that observed in a group of 747 women recruited for a population-based study. The screening algorithm used to diagnose CD was based on a 3-level screening using type IgA and IgG antigliadin antibodies (AGA) in all the patients (1st level) followed by antiendomysial antibodies (EmA) and total IgA (2nd level) of samples testing positive, and intestinal biopsy of positive cases (3rd level). At the end of the serological screening, only 1 of 127 osteoporotic women was eligible for jejunal biopsy showing a characteristic celiac flat mucosa (prevalence 7.9 x 1,000; 95% CI 0.2-43.1). In addition, CD was diagnosed in 6 of 747 women of the population-based study (prevalence: 8.0 x 1,000; 95% CI 3.3-18.3). There was no significant difference between the two groups. Therefore, our study showed that the prevalence of CD in postmenopausal osteoporotic women was lower than that reported in previous studies and similar to that of the general population. In conclusion, although the relatively small size of the group tested does not allow us to be conclusive, the results suggest that a case finding policy in postmenopausal osteoporosis would have a high cost/benefit ratio except for patients not responding to conventional therapies, or presenting borderline laboratory results.

Azathioprine in refractory sprue: results from a prospective, open-label study

OBJECTIVE:Refractory sprue is a rare and severe malabsorptive disorder that mimics celiac disease but is refractory to a gluten-free diet and is without initial evidence of overt lymphoma. Treatment is largely empiric and often ineffective, with steroids and immunosuppression being the mainstream therapeutic options. The aim of this study was to evaluate prospectively the effect of azathioprine on a group of patients diagnosed with refractory sprue.METHODS:We studied seven consecutive patients (five women and two men) with a well-defined diagnosis of refractory sprue and a lack of response to oral or parenteral steroids. At diagnosis, five patients had endoscopic evidence of ulcerative jejunitis, and five underwent exploratory laparotomy for exclusion of malignancies. The characteristic monoclonal TCRγ gene rearrangement was shown in five of six patients studied. Patients were treated for a mean of 11 months (range 8–12 months), and clinical, biochemical, molecular, and histological parameters were reassessed at the end of the trial. The study was a prospective, open-label, non-placebo-controlled study using azathioprine (2 mg/kg/day) plus oral prednisone (1 mg/kg/day). A gluten-free diet (n = 7) as well as enteral (n = 6) and parenteral nutrition (n = 5) were administered during the trial.RESULTS:After treatment, five patients had a complete clinical remission, and biochemical and nutritional parameters were significantly improved. Steroids were tapered after the onset of azathioprine, and no patient was on steroids at the end of the trial. Intestinal histology improved significantly in all cases (normal histology in three cases and minor infiltration in the lamina propria in two). Two patients did not respond to treatment at any time and died in months 10 and 9, of an irreversible ventricular fibrillation and sepsis, respectively. No overt lymphoma was demonstrated during the follow-up.CONCLUSIONS:The present study confirms earlier anecdotal reports on the efficacy of azathioprine in refractory sprue, with clear clinical and histological improvement shown in most patients. However, monoclonality persisted after treatment. We consider that a larger number of patients should be evaluated before a definitive recommendation is adopted for use of this drug in refractory sprue.