Alimentary Pharmacology & Therapeutics | 2021
Editorial: towards an understanding of increased mortality in coeliac disease
Abstract
Increased disease-specific mortality and morbidity underpins efforts to improve medical diagnosis and treatment. In contrast to some other serious digestive diseases such as ulcerative colitis,1 coeliac disease is associated with increased mortality.2 New data addressing co-morbidity and mortality associated with coeliac disease are welcome, given the relative absence of advances in diagnosis and management of coeliac disease. Recently, Lebwohl et al confirmed an increased overall risk of death in a Swedish cohort of 49 829 patients with coeliac disease; hazard ratio (HR) 1.21.3 Earlier this year, Koskinen et al reported that, in 12 803 adults diagnosed with coeliac disease in Finland between 2005 and 2014, increased mortality was limited to the first 2 years after diagnosis.4 These findings are informative, but whether they apply to less affluent or more diverse countries without publicly funded health care is not clear. The study of Schneider et al in this journal addresses whether patients diagnosed with coeliac disease have an increased risk of death and specific co-morbidities, and if disease-associated genetics predict patients most at risk.5 They utilised the UK Biobank resource, which collects genetic and “phenotypic” data linked to health records.6 Approximately 500 000 individuals from across the United Kingdom, aged between 40 and 69 were recruited from 2006 to 2010, including 0.5% with coeliac disease. Human leucocyte antigen (HLA)-associated diseases are a particular focus for the UK Biobank. The related group of cell surface proteins in the HLA system is responsible for regulating antigen recognition by T lymphocytes. In coeliac disease, specific gluten peptides presented by HLA-DQ2.5 are recognised by gluten-specific CD4+ T cells, and cause systemic cytokine release and acute digestive symptoms when patients consume gluten.7,8 In the UK Biobank, as expected, coeliac disease had an exceptionally strong association with the genes encoding HLA-DQ2.5.6 Schneider et al showed that coeliac disease is associated with an increased and, relative to other recent studies, rather high allcause risk of death (HR 1.6). Altogether, they linked coeliac disease to increased risk of death related to cancer, respiratory and cardiovascular diseases, and determined 225 co-morbidities. The risk of lymphoproliferative disease was particularly prominent, and is of interest because it is linked to a higher gene dose for HLA-DQ alleles associated with coeliac disease. Causality cannot be inferred from association studies. What intervention might address the increased mortality in patients with coeliac disease is not clear, or whether some of the more serious, genetically-related autoimmune diseases affecting patients with coeliac disease account for much of the mortality risk. What we do know is that unrecognised coeliac disease can be diagnosed earlier and that the gluten-free diet reduces intestinal inflammation. However, evidence is mounting that many “well controlled” patients with treated disease have persistent villous atrophy when high quality quantitative histology is performed,9 and more than 80% of these patients have symptomatic or asymptomatic systemic cytokine release after moderate gluten exposure.10,11 A mechanistic explanation for co-morbidities responsible for excessive mortality in coeliac disease is needed. The study of Schneider et al is an important step to considering genetic risk factors.