Mortality In Celiac Disease Research Articles

Systematic review with meta-analysis: Cause-specific and all-cause mortality trends across different coeliac disease phenotypes.

Data on mortality in coeliac disease are contrasting. To systematically review the literature on all-cause and cause-specific mortality in coeliac disease compared to the general population, and evaluate differences across clinical phenotypes, geographical regions, and over time. We searched PubMed and Embase from 1 January 1970 to 31 December 2022 for eligible studies reporting on all-cause and cause-specific mortality in coeliac disease compared to the general population or controls. The protocol was registered on Open Science Framework (https://doi.org/10.17605/OSF.IO/852DN). We included 25 studies. All-cause mortality (HR 1.16, 95% CI 1.05-1.27, I2 = 89%), mortality due to malignancies (HR 1.21, 95% CI 1.08-1.36, I2 = 65%) and respiratory disease (HR 1.39, 95% CI 1.04-1.86, I2 = 76%) were increased. Mortality due to non-Hodgkin lymphoma (HR 10.14, 95% CI 2.19-46.88, I2 = 96%) was markedly increased. Mortality significantly decreased in recent decades: 1989-2004 (HR 1.61, 95% CI 1.27-2.03, I2 = 91%), 2005-2014 (HR 1.16, 95% CI 0.99-1.36, I2 = 89%), 2015-2022 (HR 1.19, 95% CI 1.05-1.35, I2 = 93%). All-cause mortality was not increased in dermatitis herpetiformis (HR 0.85, 95% CI 0.73-0.99, I2 = 40%) and undiagnosed coeliac disease (HR 1.09, 95% CI 0.95-1.25, I2 = 0%). Mortality was increased in the UK (HR 1.23, 95% CI 1.03-1.47, I2 = 91%) but not Scandinavia (HR 1.01, 95% CI 0.91-1.13, I2 = 81%). Limitations include high heterogeneity and lack of data for many countries. Mortality in coeliac disease is increased, predominantly due to malignancies-particularly non-Hodgkin lymphoma-although differing significantly across disease phenotypes. Mortality of patients with coeliac disease has significantly decreased in recent decades. These results may influence diagnosis and management.

Mortality and causes of death in different celiac disease phenotypes during long-term follow-up.

Celiac disease has been associated with increased mortality, but data on long-term mortality are scarce. To determine long-term mortality in celiac disease. The study cohort consisted of all celiac disease patients (n=1,392) diagnosed in Tampere University Hospital catchment area 1960 - 2000. Patients were categorized into subgroups based on demographic (age, gender, decade of diagnosis) and celiac disease characteristics (e.g., phenotype, severity of villous atrophy) collected from medical records. Overall and cause-specific mortality was compared to those of age-, sex-, and place of residence matched reference individuals (n=4,177) over time. During the 41 years of follow-up (median 26.5 years), 376 celiac disease patients and 1,155 reference individuals died. All-cause mortality was not increased (hazard ratio (HR) 0.96, 95% confidence intervals (CI) 0.85-1.08). Mortality from lymphoproliferative diseases and diseases of the central nervous system was increased (HR 2.42, 95% CI 1.38-4.24 and HR 2.14, 95% CI 1.05-4.36 respectively) while the risk from alcohol related diseases was decreased (HR 0.31, 95% CI 0.09-1.00). Examination of various celiac disease phenotypes revealed no significant differences in mortality CONCLUSIONS: Overall mortality was not increased in any celiac disease phenotype during a very long-term follow-up.

Phenome of coeliac disease vs. inflammatory bowel disease

Coeliac disease (CeD) is characterized by gliadin-induced intestinal inflammation appearing in genetically susceptible individuals, such as HLA-DQ2.5 carriers. CeD, as well as other chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis, has been associated with increased morbidity and mortality, but the causes are unknown. We systematically analysed CeD-associated diagnoses and compared them to conditions enriched in subjects with CD/UC as well as in HLA-DQ2.5 carriers without CeD. We compared the overall and cause-specific mortality and morbidity of 3,001 patients with CeD, 2,020 with CD, 4,399 with UC and 492,200 controls in the community-based UK Biobank. Disease-specific phenotypes were assessed with the multivariable Phenome Wide Association Study (PheWAS) method. Associations were adjusted for age, sex and body mass index. All disease groups displayed higher overall mortality than controls (CD: aHR = 1.91[1.70–2.17]; UC: aHR = 1.32 [1.20–1.46]; CeD: aHR = 1.38 [1.22–1.55]). Cardiovascular and cancer-related deaths were responsible for the majority of fatalities. PheWAS analysis revealed 166 Phecodes overrepresented in all three disorders, whereas only ~ 20% of enriched Phecodes were disease specific. Seven of the 58 identified CeD-specific Phecodes were enriched in individuals homozygous for HLA-DQ2.5 without diagnosed CeD. Four out of these seven Phecodes and eight out of 19 HLA-DQ2.5 specific Phecodes were more common in homozygous HLA-DQ2.5 subjects with vs. without CeD, highlighting the interplay between genetics and diagnosis-related factors. Our study illustrates that the morbidity and mortality in CeD share similarities with CD/UC, while the CeD-restricted conditions might be driven by both inherited and acquired factors.

The Gut Feeling of the Heart: Pathophysiological Pathways in the Gut-heart Axis in Celiac Disease

The chain of events, starting from nutrients that change microbiome/dysbiome ratio followed by their secreted mobilome and ending with the leaky gut syndrome, can be applied for cardiovascular diseases. The Gut-heart axis is only one avenue where intestinal luminal eco-events induce remote organ's pathology. The present editorial highlights the mechanisms and potential pathways in the nutrients-microbiota-endocrine-cardiovascular axis that might affect human heart morbidity and mortality in celiac disease.

Letter: mucosal healing and mortality in coeliac disease

We read the interesting paper by Lebwohl et al.1 The authors concluded that there was no association between persistence of villous atrophy and mortality in coeliac disease (CD). However, the study design and the interpretation of results raise some concerns. In spite of the impressive number of patients evaluated, it is of note that only 26% of the CD-diagnosed patients during the study period had a follow-up biopsy, with the reason why these biopsies were taken unknown and therefore, as the authors mention in their discussion, ascertainment bias cannot be excluded. It has recently been emphasised that small bowel biopsy remains the gold standard for monitoring mucosal healing in CD.2, 3 Persistent villous atrophy was associated with a more than threefold increased risk of osteoporosis, refractory CD and malignancies irrespective of symptom resolution on a gluten-free diet (GFD).4 Thus, the question that emerges is whether the CD patients in this study cohort were adequately followed up. A recent paper showed that medical follow-up evaluation in patients with CD is highly variable and often inadequate. In fact, follow-up consistent with current American Gastroenterology Association recommendations was observed in only 35% of patients.5 Currently, clear guidelines on when to repeat small-bowel biopsy are lacking. However, a systematic review of studies reporting the long-term management of CD suggested that follow-up biopsy at 1–2 years after commencement of the GFD is recommended, and that if histological improvement is incomplete, biopsies probably should be performed again in 1–2 years.6 Thus, the evaluated cohort of patients would not be useful to assess how persistent villous atrophy influenced mortality in CD, as the rate of follow-up small-bowel biopsy was quite low, the reason why these biopsies were taken was unknown, and there were no additional follow-up biopsies performed when histological improvement was incomplete. Likewise, follow-up biopsy in the study by Lebwohl et al.1 demonstrated that there was persistent villous atrophy in 43% of the cohort. It is reasonable to think that in these patients, dietary measures to improve GFD adherence were taken, as lack of dietary adherence is considered the main reason for persistence of villous atrophy. Improvement in dietary adherence would have influenced survival, and decreased mortality to the level of patients who have mucosal healing. In this sense, the problem in the long-term management of CD is the nondiagnosed persistent villous atrophy. Only once it is detected, can the opportune dietary measures be established. Declaration of personal and funding interests: None.

Letter: complications of coeliac disease despite a gluten‐free diet

In their recent paper, Lebwohl and colleagues report an interesting finding: persistent villous atrophy (VA) does not seem to be associated with increased mortality in coeliac disease (CD).1 This conclusive statement is quite surprising. As already stated by the authors, CD patients are at risk of earlier death,2, 3 and failure in mucosal healing has been thought to be the main factor.4, 5 This study seems to call into question this consolidate hypothesis, and it deserves some comments from a clinical practice's point of view. We know that histological recovery takes different times, according to the age when gluten-free diet (GFD) has started. In our experience, subdividing the patients according to age, only the younger patients (5–30 years) showed significant improvement of histology within 12 months (P < 0.034); older patients (>30 years) showed histological improvement, but this was not statistically significant, even after 24 months on a GFD.6 Gluten-free diet is generally advised to CD patients for three main reasons: treating symptoms related to the disease; preventing immunological gluten-related disorders; and preventing neoplastic complications. GFD and adherence to diet are considered the key factors in obtaining mucosal healing and in preventing occurrence of complications.7, 8 In our experience, the time to the occurrence of complications with GFD seems to be related to type of disease rather than to the severity of the histological lesion at the time of the diagnosis. In fact, considering the time of appearance of complications after GFD had started, complications occurred after a mean/median time with GFD of 6.5/5 years [standard deviation (s.d.) ± 5.08] in classical CD, and after a mean/median time of 3.5/4 years (s.d. ± 1) in subclinical CD. However, looking at the compliance to GFD in patients developing complications, we found that 6/14 (42.9%) patients with classical CD were not fully compliant with GFD, whilst 2/4 (50%) of subclinical CD were not fully compliant (P = n.s.).9 In light of our and Lebwohl's experience, should a GFD still be advised to prevent complications? Despite the retrospective design, Lebwohl's study calls into question whether and why an increased complication rate (increased mortality rate included) occurs in CD. Furthermore, confirmative and prospective studies are, therefore, welcomed. Declaration of personal and funding interests: None.

Mucosal healing and mortality in coeliac disease

Coeliac disease (CD), characterised by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if mortality is influenced by mucosal recovery. To determine whether persistent VA is associated with mortality in CD. Through biopsy reports from all pathology departments (n=28) in Sweden, we identified 7648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5years following diagnosis. We used Cox regression to examine mortality according to follow-up biopsy. The mean age of CD diagnosis was 28.4; 63% were female; and the median follow-up after diagnosis was 11.5years. The overall mortality rate of patients who underwent follow-up biopsy was lower than that of those who did not undergo follow-up biopsy (Hazard Ratio 0.88, 95% CI: 0.80-0.96). Of the 7648 patients who underwent follow-up biopsy, persistent VA was present in 3317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared with those with mucosal healing (HR: 1.01; 95% CI: 0.86-1.19). Mortality was not increased in children with persistent VA (HR: 1.09 95% CI: 0.37-3.16) or adults (HR 1.00 95% CI: 0.85-1.18), including adults older than age 50years (HR: 0.96 95% CI: 0.80-1.14). Persistent villous atrophy is not associated with increased mortality in coeliac disease. While a follow-up biopsy will allow detection of refractory disease in symptomatic patients, in the select population of patients who undergo repeat biopsy, persistent villous atrophy is not useful in predicting future mortality.

Gluten-Free Diet: Imprudent Dietary Advice for the General Population?

As of April 20, 2012, Amazon.com listed 4,765entriesforthetopic“gluten-free.”AGooglesearchatthesametime for “gluten-free diet” produced more than 4.2 millionresults. The number-one reason consumers cite for buyinggluten-freeproductsisthattheyareperceivedtobehealthierthan their gluten-containing counterparts.

396 Mucosal Healing and Mortality in Celiac Disease

396 Mucosal Healing and Mortality in Celiac Disease

* Vascular risk profile in incident coeliac disease and change with gluten-free diet

IntroductionVascular disease is the most common cause of mortality in coeliac disease.1 Despite recent studies observing people with diagnosed coeliac disease have lower total cholesterol and are less likely to...

Mortality in celiac disease

Although the prevalence rates of celiac disease tend to be very similar in different Western populations, mortality rates for this disease vary widely. In this Review we focus on the papers that have addressed this issue so far. We evaluated mortality rates in different forms of celiac disease, such as symptomatic celiac disease, unrecognized celiac disease, dermatitis herpetiformis and refractory celiac disease. We also evaluated the role of possible protective factors, such as adherence to a gluten-free diet, early diagnosis and severity of clinical presentation. Finally, we noticed that the mortality rate for celiac disease seems to be higher in Southern than in Northern Europe and seems to correlate with 'national' gluten consumption. To explain these differences, we propose a hypothesis that links mortality rates to the amount of gluten consumed not only after but also before the diagnosis of celiac disease.

Small-Intestinal Histopathology and Mortality Risk in Celiac Disease

Studies of mortality in celiac disease have not taken small-intestinal pathology into account. To examine mortality in celiac disease according to small-intestinal histopathology. Retrospective cohort study. We collected data from duodenal/jejunal biopsies taken between July 1969 and February 2008 on celiac disease (Marsh stage 3: villous atrophy; n = 29,096 individuals) and inflammation (Marsh stage 1-2; n = 13,306) from all 28 pathology departments in Sweden. A third cohort consisted of individuals with latent celiac disease from 8 university hospitals (n = 3719). Latent celiac disease was defined as positive celiac disease serology in individuals with normal mucosa (Marsh stage 0). Through linkage with the Swedish Total Population Register, we estimated the risk of death through August 31, 2008, compared with age- and sex-matched controls from the general population. All-cause mortality. There were 3049 deaths among patients with celiac disease, 2967 with inflammation, and 183 with latent celiac disease. We found an increased hazard ratio (HR) for death in celiac disease (HR, 1.39; 95% confidence interval [CI], 1.33-1.45; median follow-up, 8.8 years), inflammation (HR, 1.72; 95% CI, 1.64-1.79; median follow-up, 7.2 years), and latent celiac disease (HR, 1.35; 95% CI, 1.14-1.58; median follow-up, 6.7 years). The absolute mortality rate was 10.4 (95% CI, 10.0-10.8) per 1000 person-years in celiac disease, 25.9 (95% CI, 25.0-26.8) in inflammation, and 6.7 (95% CI, 5.7-7.6) in latent celiac disease. Excess mortality was 2.9 per 1000 person-years in celiac disease, 10.8 in inflammation, and 1.7 in latent celiac disease. This risk increase was also seen in children. Excluding the first year of follow-up, HRs decreased somewhat. Risk of death among patients with celiac disease, inflammation, or latent celiac disease is modestly increased.

Mortality in Celiac Disease, Intestinal Inflammation, and Gluten Sensitivity

CELIAC DISEASE DEVELOPS IN GENETICALLY PREDISposed individuals as a response to ingested gluten. Gluten is the term for the storage proteins of the cereal grains wheat, rye, and barley. While virtually 100% of the population ingests these grains in one form or another and 30% to 40% of the population carry the genetic markers of the disease (HLA-DQ2 or type 8), only 2% to 3% of those with genetic markers develop the disease. This indicates that other genetic factors and environmental precipitants are necessary for disease expression. These factors are largely unknown, although breastfeeding, timing of gluten introduction, and gastrointestinal infections in childhood have been incriminated, at least in the development of childhood celiac disease. The diagnosis of celiac disease is dependent on finding characteristic, although not specific, pathological findings in duodenal biopsies. These changes include inflammatory changes within the small-intestinal epithelium (intraepithelial lymphocytosis) and the lamina propria as well as various degrees of villous atrophy. A range of pathological abnormalities exists, from intraepithelial lymphocytosis with normal villous architecture to total villous atrophy, all of which are considered part of the spectrum of gluten enteropathy or celiac disease. However, there are several causes of intraepithelial lymphocytosis without villous atrophy in addition to celiac disease, such as Helicobacter pylori infection and tropical sprue. It is therefore difficult to diagnose celiac disease in the setting of intestinal inflammation when villous atrophy is absent. But in some clinical settings, such as the presence of symptoms, positive serologic results, and even the appropriate HLA type, patients with these inflammatory changes receive a diagnosis of celiac disease. Serologic blood tests that include antigliadin, tissue transglutaminase (tTG), and endomysial antibodies are used for triaging individuals for endoscopic biopsy. The tTG and endomysial antibodies are sensitive and specific for celiac disease, while antigliadin antibodies are not as sensitive or specific. Celiac disease is common, occurring in about 1% of the population, although the majority of cases are undiagnosed. The number of persons actually diagnosed as having celiac disease varies from country to country, depending on physician awareness of the varied clinical manifestations and the availability of blood tests for the condition. The rate of diagnosis is high in some European countries such as Finland, where in some regions 70% of cases are diagnosed. Within the United States, the rate of diagnosis is increasing, both in adults and children, although only a small fraction (estimated at 5%) of cases are diagnosed. Recent evidence from both Finland and the United States has demonstrated that the prevalence of celiac disease has increased markedly over a relatively short time. In the United States, the prevalence of celiac disease has increased 4-fold in the last 50 years. These data are based on the analysis of stored serum samples and reflect a true increase in the prevalence of the disease, not just the number of individuals who are given diagnoses. The reason for this increase is not clear but may be related to environmental factors such as the changing nature of gluten or other factors related to diet. Accompanying this increase in disease prevalence is a change in the clinical manifestations, so that the classic presentation of diarrhea and malabsorption syndrome is now less common than other presentations. The disease now manifests more often as a multisystem disorder. Anemia, osteoporosis, peripheral neuropathy or ataxia, irritable bowel syndrome, and dyspepsia are all possible presentations. Many patients are asymptomatic, with the disease detected by screening performed because of their presence in a highrisk group such as being a family member or having an associated autoimmune disease, type 1 diabetes, or Down syndrome. Increasingly, those with autoimmune thyroid disease are also screened. Patients with undiagnosed or diagnosed celiac disease appear to have an increased mortality risk. Based on studies that have examined stored serum samples for tTG antibodies and correlated the results with mortality data, those with

Mortality in Celiac Disease, Intestinal Inflammation, and Gluten Sensitivity

Mortality in Celiac Disease, Intestinal Inflammation, and Gluten Sensitivity

Long-Term Mortality in People With Celiac Disease Diagnosed in Childhood Compared With Adulthood: A Population-Based Cohort Study

To explore whether the excess mortality in celiac disease is related directly to the disease and duration of gluten exposure before diagnosis we have examined the long-term mortality experience of people with celiac disease diagnosed as children and as adults. Two hundred eighty-five children and 340 adults diagnosed with celiac disease were followed until death, loss to follow-up, or December 31, 2004. We calculated standardized mortality ratios (SMRs). All-cause mortality more than 5 yr after diagnosis was increased threefold in children (SMR 3.32, 95% CI 2.05-5.07) compared with only a 38% increase in adults (SMR 1.38, 95% CI 1.16-1.63). This excess mortality in children was primarily because of an increased risk of death from accidents, suicide, and violence (seven deaths, SMR 3.22, 95% CI 1.29-6.63), cancer (five deaths, SMR 3.72, 95% CI 1.21-8.67), and cerebrovascular disease (two deaths, SMR 10.03, 95% CI 1.21-36.00). Children diagnosed with celiac disease had a threefold increased risk of long-term mortality. This is in marked contrast to the experience of adult celiac disease where the long-term increase of mortality was modest. The increased mortality in children from external causes may reflect behavioral change associated with coping with a chronic disease and its treatment.

Mortality and causes of death in celiac disease in a Mediterranean area.

No data on mortality in celiac disease are currently available in southern Europe. Our aim was to evaluate mortality and the cause of death in adult celiac disease in a Mediterranean area. In all, 228 adults with celiac disease were histologically diagnosed in our department from 1980 to 1997. Full information on their state of health was obtained in 216 of 228 patients. A tabulation of patient-years at risk was constructed in terms of age at diagnosis and the interval from diagnosis. Standardized mortality ratio was calculated by dividing the number of observed deaths by the number of expected deaths. Twelve deaths were observed, whereas 3.12 deaths were expected (SMR = 3.8; 95% CI 2-7). The increased mortality was mainly observed within four years from diagnosis (8 observed; 1.4 expected) (SMR = 5.8; 95% CI 2.5-11.5). Twelve tumors were observed (six lymphomas). In conclusion, mortality from adult celiac disease in our geographical area is increased compared with the general population, and this increased risk seems due to non-Hodgkin's lymphoma.

Mortality in celiac disease in a mediterranean area

Mortality in celiac disease in a mediterranean area

Mortality in celiac disease

The mortality experienced by a cohort of 653 patients with celiac disease in Edinburgh and the Lothian region has been analyzed. Mortality overall was 1.9-fold (95% confidence limits, 1.5–2.2) that of the general population (115 deaths observed, 61.8 expected; p < 0.0001). The increased mortality was greatest within 1 yr of diagnosis of celiac disease and steadily declined over time with the excess mortality being concentrated at ages 45–54 yr in men and 55–64 yr in women. Celiac disease was mentioned on the death certificate in 33 cases but in only 10 was it given as the underlying cause of death. Of 17 deaths from lymphoproliferative diseases (0.55 expected, p < 0.001), 8 occurred within 2 yr of diagnosis of celiac disease compared with 8 (0.37 expected, p < 0.001) occurring >5 yr after diagnosis. Esophageal cancer was certified as the cause of four deaths (0.47 expected, p < 0.01). In men mortality from all other malignant disease was also increased (15 deaths observed; 6.4 expected, p < 0.01), but most of these deaths occurred within 5 yr of the diagnosis of celiac disease. In contrast, there was no deficit in deaths from ischemic heart disease or stroke and the mortality rate in those diagnosed in childhood as having celiac disease was similar to the general population.