Author(s): Michael X Ma [*] 1 , Mina John 2 3 , Geoffrey M Forbes 4 5
celiac disease; combination serology; diagnosis; gluten-free diet; nonceliac gluten sensitivity; nonresponsive celiac disease; novel investigations
Celiac disease (CD) is a chronic immune-mediated disorder characterized by gastrointestinal pathology with associated systemic manifestations. In genetically susceptible individuals, exposure to dietary gluten typically results in small-bowel mucosal inflammation, villous atrophy and crypt hyperplasia. The presenting clinical features of CD are varied, which contribute to underrecognition of this condition. Untreated CD can cause significant and varied medical complications, with associated negative impacts on psychosocial well-being and quality of life. Timely treatment of CD through early and accurate diagnosis, therefore, has significant clinical and economic benefits to individuals and the broader community. This article will review current diagnostic algorithms for CD and discuss diagnostic challenges in patients with possible CD, and those in whom the diagnosis has previously been established. We review recent controversies with respect to nonceliac gluten sensitivity and diagnosis based on combination serology alone; we also suggest that projected developments in CD diagnostics may occur over the next 5 years.
Tip of the iceberg
CD has traditionally been considered a disease affecting Caucasians of northern European descent with prevalence of about 1% in these populations  . However, epidemiologic studies increasingly demonstrate CD as a global disease with a heterogeneous prevalence [2-6] . For example, a European prevalence screening study based upon serology revealed that the prevalence of CD is relatively high in Finland (2.4%), and low in Germany (0.3%) and Italy (0.7%)  .
Serologic screening studies have reported an increasing incidence of CD to the magnitude of two- to fivefold over the past 50 years [8,9] . This increase is multifactorial: a true rise in disease incidence over time, increasing awareness of CD among clinicians and the general population, and greater utilization of serological tests identifying patients with either atypical presentations or who are asymptomatic. Yet, population studies suggest that the majority of patients with CD remain undiagnosed. For example, although 70% of individuals with CD were diagnosed in a Finnish study  , only 5% were diagnosed in a community-based study from the USA  . Although CD prevalence is relatively high in Finland, implementation of education programs encouraging primary care medical staff to identify at-risk groups and subtle disease manifestations also aided greater CD detection in the former study  . Given, CD is a treatable condition, improved disease detection will have significant public health benefits but still remains a major challenge.
Setting the scene: current gold standard diagnosis
The current CD diagnostic model is based on the integration of clinical suspicion, positive serological tests, diagnostic duodenal biopsy and presence of the HLA-DQ2 or -DQ8 haplotype. Guidelines appropriately state that individuals should maintain a gluten containing diet prior to testing to minimize the risk of false-negative serology or histology results [12,13,101,102] . However, there is little evidence defining the quantity and duration of dietary gluten intake required. A minimum of 6 weeks exposure to gluten containing foods in at least one...