The present study identified independent factors associated with celiac disease in Saudi population, including family history, diabetes mellitus, hypothyroidism, respiratory infections, and H. pylori infection. In addition, diagnostic accuracy of serological tests showed superiority of anti-tissue transglutaminase IgA as a screening tool for CD.
Our study findings concur with a previous population based study that reported a 2.5 times higher risk of CD among patients who had first degree relatives affected by CD in USA [14]. However, the higher magnitude of CD risk observed among patients with familial link, in this study, indicate a population specific greater risk of CD in Saudi Arabia.
Furthermore, it is interesting to note the significant association between diabetes mellitus, hypothyroidism and CD in this study. Among diabetic CD cases, predominant number of patients had type 1 diabetes mellitus (T1DM). Similar findings were observed in previous studies, where prevalence of CD was 17.9% based on serology, and 11.3% based on biopsy among T1DM children in Saudi Arabia [25]. In addition, our results are consistent with previous studies that showed higher prevalence of hypothyroidism among celiac disease patients in Italy, Sweden, Brazil and other countries [26–30]. A 3-fold higher prevalence of hypothyroidism was observed among CD cases (12.9% vs 4.2% in controls) in an Italian multicenter study [26], whereas the risk of hypothyroidism was over 4-fold in a Swedish study [27]. In a meta-analysis, a significant increase in the prevalence of hypothyroidism was found in CD patients compared to controls (OR = 3.38, 95% CI: 2.73–4.20) [30]. In particular, CD was linked to autoimmune thyroid disease [29, 31–33]. Our findings support the link between autoimmune disorders and CD, possibly through a shared genetic predisposition in susceptible individuals [34]. It is noteworthy that genetic risk of CD was related to HLA genotypes DQ2 (90%) and DQ8 that could account for the link to autoimmune disorders such as T1DM and autoimmune thyroid disease [34].
Although the present study found a positive association, the evidence for association between H. pylori infection and CD has been controversial. Some studies reported H.pylori as a risk factor [35], some as a protective factor [36, 37], while others found no association [38]. Konturek et al., reported a higher frequency of H. pylori in patients with CD than in controls (26% vs. 20%) in Germany [35]. However, other studies, including a recent meta-analysis found an inverse relationship between H. pylori and CD; pooled OR was 0.56 indicating a protective effect [36, 37]. Uyanikoglu et al., compared the prevalence of H.pylori in CD positive and negative patients and found no significant difference [38]. But, small sample size of the cases (n = 31) would have limited the study power in detecting any significant difference. Although mechanistic evidence indicate a possible role of molecular mimicry in triggering autoimmune response in H. pylori infection, future research should address the ambiguity in evidence pertaining to development of CD in genetically susceptible individuals [38–40].
In addition, the positive association observed between respiratory infections and CD, and lack of association with enteric infections caused by Shigella and Salmonella species indicate diverse role played by infectious agents in triggering autoimmune response. Our results were in agreement with an Italian cohort study, which reported a 2-fold higher risk of CD among high-risk newborns (with a family history) who experienced respiratory infections during their first 2 years of life [41]. Further studies are needed to confirm these findings, and relevant mechanistic pathway in high-risk groups.
The present study also assessed diagnostic accuracy of screening tests for CD, and superiority of TTG-IgA as a screening tool is evident. This suggest that, in a resource-constrained setting, TTG- IgA could be the optimal CD screening tool. Based on our data, the best cut-off is > = 12.5 U/ml for this marker. However, our proposed cut-off was much lower than that was reported by Al-Hussaini et al., (anti-TTG-IgA of > 63 U/ml) [25], likely due to differences in population under study; Al-Hussaini et al., study was based on high risk pediatric patients with type 1 DM, whereas the present study was based on both adults and children. It is interesting to note that the sensitivity (91.6%) and specificity (93.6%) of TTG-IgA was higher in high-risk population, indicating the need to identify broader high-risk groups based on associated factors [25].
To the best of our knowledge, this is the first case-control study to investigate the factors associated with CD in Saudi Arabia. The strength of this study is selection of CD cases and controls without CD based on gold-standard intestinal biopsy. In contrast, many studies in the past used cases based on seropositivity and controls based on clinical absence of disease. Thus, it is difficult to exclude the potential of misclassification bias in those studies. In addition, we ensured absence of CD among controls by selecting patients with normal duodenal biopsy, thereby avoiding inclusion of asymptomatic celiac patients as controls.
This study has some limitations that should be acknowledged. The associations of CD with comorbid conditions should be interpreted with caution, and further studies are needed to confirm the association of CD with the comorbidities investigated in this study. This is a one-center hospital-based study, thereby limiting the generalizability of study findings. However, KAMC is a large referral tertiary medical city that caters to a wide range and spectrum of patients that may typically represent patients with CD in Saudi Arabia. The known limitations of the retrospective design apply to this study. Prospective multicenter studies are needed to confirm our findings.
CD remain largely under diagnosed [42–45]. Our study findings could aid in identifying high-risk groups for screening. Future studies in the Arab world should further explore CD associated risk factors in diverse populations, accuracy of available screening tests, and determining the role of environmental triggers, such as indoor and outdoor air pollution, life style and dietary habits associated on CD.