Among subjects whose disease status was unknown, 16,886 Olmsted County, Minnesota residents ≥ 50 years of age who had consented to use of their serum for research were screened for CD. In total, 163 (1.0%) individuals tested positive for tTGA and underwent confirmatory EMA testing, while 143 had borderline tTGA levels (2.0–4.0 U/mL) and also were EMA tested. Based on a combined serology status of both the tTGA and EMA result, 39 subjects were considered equivocal and were excluded from subsequent analyses (final denominator, 16847). None of the 39 subjects were subsequently diagnosed with CD. A total of 129 subjects demonstrated a combined seropositive result for CD. Thus the seroprevalence of undiagnosed CD in our study population is 0.8 (95% CI, 0.6%–0.9%).
Patients without general research authorization for use of their medical records were excluded from subsequent analyses, including 2 seropositives and 278 potential controls. For the remaining 127 undiagnosed CD cases (51% female; median age=63.0 years; range, 51.7–87.7), 254 matched controls were selected for comparison (). Upon review, 20 seropositive patients were subsequently diagnosed (clinically) with CD (10-year KM rate, 15.2%; 95% CI, 8.2%–22.1%) after a median (range) of 10.3 (0.0–12.9) years of follow-up. Of note, no controls had yet to be subsequently diagnosed with CD.
Demographics of study participants
Undiagnosed CD was associated with decreased lumbar spine T-scores when compared to controls −1.7 vs. −0.9; OR=0.64; 95% CI, 0.48–0.85) () and an increased risk of osteoporosis () These patients also demonstrated higher rates of hypothyroidism. Conversely, undiagnosed CD patients had lower weight and BMI values (median value, 26.4 vs. 27.4) and while not statistically significant, a reduced rate of glucose intolerance. Laboratory evaluation showed undiagnosed CD was associated with reduced levels of cholesterol (median value, 200.0 vs. 213.0) and ferritin (25.0 vs. 78.5) ().
Impact of undiagnosed celiac disease on lumbar spine T-score
Summary of outcomes of undiagnosed celiac disease cases compared to serology-negative controls
Laboratory evaluation of patients with undiagnosed celiac disease cases compared to serology negative controls
Diagnosed and symptomatic celiac disease is known to be associated with an increased risk of cancer.5, 7
Upon review of the medical records, there was not a significantly increased risk of cancer detected in the undiagnosed CD patients compared to controls. The total number of cases identified as having cancer was 31 (24.4%) in the undiagnosed group compared to 51 (20.1%) in the controls (OR=1.29; 95% CI, 0.77–2.15). Two patients in the seropositive group were found to have a CD-associated malignancy (both small bowel lymphoma) as did two in the seronegative group (both esophageal cancer). Of the two undiagnosed CD patients with small bowel lymphoma, one was found to have a T-cell lymphoma.
Patient status (undiagnosed CD vs. controls) was not found to be associated with potential CD symptoms (). In particular, there was no difference in the proportion reported as having irritable bowel syndrome (10.4% vs. 12.6%) or experiencing weight loss (11.2% vs. 7.8%) around the time of serum draw. Furthermore, diarrhea was actually less prevalent, albeit not significantly, in undiagnosed cases than controls (21.4% vs. 26.2%). Overall, five seropositive subjects and none of the controls had a prior diagnosis of dermatitis herpetiformis.
Classic celiac disease symptoms in undiagnosed celiac disease cases compared to serology negative controls
In addition, undiagnosed CD was not found to be associated with an increased rate of all-cause mortality (HR=0.80; 95% CI, 0.45–1.41) or cancer –related mortality (). In particular, undiagnosed CD cases did not demonstrate a higher rate of mortality that was caused by any cancer, visceral types of cancer, or CD-associated types of cancer.
Association between undiagnosed celiac disease and mortality
Of the 20 seropositive patients who were subsequently diagnosed with CD, iron deficiency (n=9, 45%) was the most common presenting symptom (). Three patients were diagnosed with CD after having been diagnosed with dermatitis herpetiformis first. Interestingly, only 3 of the 20 (15%) CD patients had presented with classic symptoms of diarrhea, malabsorption, and weight loss at the time of diagnosis. Other presenting symptoms included family history (n=3), nausea (n=1), and small bowel lymphoma (n=1). Gender was significantly associated with subsequent CD diagnosis, with 15 (75%) of these 20 being female in contrast to the nearly equally-divided gender distribution (47% female) in seropositives without a subsequent CD diagnosis (p=0.02 from a Chi-square test).
Presenting diagnosis of the 20 seropositive patients subsequently diagnosed clinically with celiac disease