Celiac disease (CD) is a chronic immune-based disease affecting primarily the absorption surface of the proximal small intestine. It is known now that CD is the most common genetically predetermined condition in humans, with a childhood prevalence of 1% in the United States and many European countries (1). Many reports have suggested major changes in the presenting symptoms of CD in both adults and children, with severe malabsorptive gastrointestinal (GI) tract symptoms becoming less common (2–4).
Historically, CD has been associated with many micronutrient deficiencies, particularly the fat-soluble vitamins (A, D, E, and K); however, in the past, CD was believed to be a rare childhood disease, which was usually diagnosed late following a period of prolonged diarrhea. With recent diagnostic advances and the ability to target asymptomatic children in high-risk groups (on the basis of family history and the presence of type 1 diabetes mellitus, immunoglobuline (Ig)A deficiency, and Down syndrome), children are being diagnosed early in the course of the disease. Hence, many present with mild non-GI symptoms or even no symptoms at all.
The rate of diagnosis of pediatric CD has also risen dramatically in the last decade (5). This may be attributable to the increased application of sensitive serologic tests that can enable earlier diagnosis, or a true increase in CD incidence may have occurred. It is important to note that some manifestations of CD can occur in the absence of any substantial overt GI symptoms. For example, bone loss (manifest most commonly as osteoporosis or classically as osteomalacia) is a common feature in adult CD and can happen in patients who have no GI tract symptoms (6). These patients may have secondary hyperparathyroidism, which is caused by vitamin D deficiency (7). There are many reports about fat-soluble vitamins and trace element deficiencies in adult patients with CD. For all of the adult patients with a new CD diagnosis, the expert opinion recommends checking for vitamin D, vitamin A, zinc, copper, folic acid (serum), and ferritin (8–11).
In pediatric patients with a new CD diagnosis, there are no clear guidelines about whether fat-soluble vitamin levels should be routinely checked, although some expert opinion suggests checking the vitamin D level. Moreover, data are limited concerning the prevalence of vitamin deficiencies in children with CD and whether routine assessment is required at diagnosis. Some data have suggested a correlation between low vitamin D level and low bone density, without a clear recommendation to check the vitamin level or bone density (12,13).
Can routine testing for vitamin deficiency at initial CD diagnosis prevent long-term complications that may result from an undiagnosed vitamin deficiency, or is it needlessly subjecting patients to multiple blood tests and increased financial burden without clear benefit? We aim to identify the frequency of fat-soluble vitamin deficiency in children diagnosed as having CD to determine whether there is any clinical value in routine testing for these deficiencies.
Pediatric patients with CD who had fat-soluble vitamin levels measured at diagnosis between 1995 and 2012 at Mayo Clinic were identified using the Mayo Clinic life science system (Rochester, MN) that allows for systematic searching of the entire electronic medical record system at Mayo Clinic. Inclusion criteria included children (0–18 years of age) at the time of diagnosis; presence of clinical or histologic evidence of CD; and determination of vitamin A, E, and D levels at the time of diagnosis. Patients without measured vitamin levels or a confirmed diagnosis of CD and adult patients were excluded from the final analysis. The study protocol was approved by the Mayo Clinic institutional review board.
Diagnosis of CD was established at Mayo Clinic using the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis and treatment of CD in children (14). All of the patients had positive celiac serologic testing (endomysial IgA antibodies or anti–tissue transglutaminase [anti-TTG] antibodies). All included patients except for 1 had a confirmatory duodenal biopsy at the time of diagnosis.
Pertinent clinical factors were collected: family history of CD, autoimmune disorders (diabetes, rheumatoid arthritis, psoriasis, thyroid disease, and systemic lupus erythematosus), and clinical symptoms (abdominal pain, diarrhea, constipation, failure to thrive [FTT], and poor weight gain). Body mass index (BMI) was also collected to help assess the nutritional status of patients and its correlation with vitamin deficiency.
Celiac serologic testing included serum IgA and anti-TTG IgA or IgG. Other collected variables included vitamin A (free retinol), D (25-hydroxy vitamin D), and E (α- tocopherol) levels, hemoglobin, hematocrit, and ferritin at the time of diagnosis of CD. Vitamin A was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with specific quantitation of retinol. Normal range for vitamin A was 0 to 6 years, 11.3 to 64.7 μg/dL; 7 to 12 years, 12.8 to 81.2 μg/dL; and 13 to 17 years, 14.4 to 97.7 μg/dL. Vitamin D was obtained using LC-MS/MS. Reference range for vitamin D was defined as <10 ng/mL (severe deficiency), 10 to 19 ng/mL (mild-to-moderate deficiency), 20 to 50 ng/mL (optimum levels) (15). Vitamin E was obtained through LC-MS/MS with specific quantitation of α-tocopherol. Normal range for vitamin E for 0 to 17 years was 3.8 to 18.4 mg/L.
Pathologic reports were reviewed in patients who had a small bowel (SB) biopsy to document the degree of villous injury and assess whether it correlated with vitamin levels. Histologic assessment was done using a modified Marsh classification (16): 0, normal SB mucosa; 1, normal villi with increased intraepithelial lymphocytosis; 2, normal villi with crypt hyperplasia; 3, partial villous atrophy; and 4, complete villous atrophy.
Continuous variables were reported as mean ± standard deviation. Analysis-of-variance (ANOVA) analysis was used as appropriate to compare the effect of different variables on the vitamin levels.
Eighty-three patients (51 girls, 32 boys) were included in the final analysis. The average age at diagnosis of CD was 12.8 ± 3.8 years in girls and 13.0 ± 3.6 years in boys. The median BMI percentile in girls ≥2 years of age was 52% (range 3%–99%) and in boys ≥2 years of age it was 57% (range 1%–99%). The median height-for-age percentile for boys was 64.1% and the median z score was 0.4, whereas the median height-for-age percentile for girls was 75.2% and the median z score was 0.7. Four boys and 9 girls had a height-for-age percentile of <10%. Baseline demographic data are shown in Table 1, and laboratory data are shown in Table 2.
In children <2 years of age (n = 6, 3 boys and 3 girls), 2 boys and 3 girls had a weight-for-height <15th percentile. In children ≥2 years of age 8 boys and 10 girls had a BMI <15th percentile.
Most patients had multiple GI symptoms, and the most reported symptoms at the time of diagnosis were abdominal pain in 49 patients (49/83, 59%) and diarrhea in 30 patients (30/83, 36%). Other clinical presentations included concern of FTT (13 patients) and poor weight gain (13 patients). Patients with either FTT or poor weight gain had a median BMI percentile of 14.5%. Symptoms present include abdominal bloating or distention (17 patients), constipation (18 patients), reflux (5 patients), and vomiting (9 patients). Family history of CD was reported in 32 patients (39%). Positive family history of celiac and other autoimmune diseases is summarized in Table 3.
Thirty-two patients had a family history of CD, 15 had a family history of type 1 diabetes mellitus, and none had trisomy 21. All of the patients had symptoms (abdominal pain, diarrhea, and FTT) at the time of presentation and none of patients had upper endoscopy because of increased risk.
Eighty-two patients had SB biopsies that showed normal villous architecture with intraepithelial lymphocytosis (Marsh 1) in 14 patients, partial villous atrophy (Marsh 3) in 37 patients, and complete villous atrophy (Marsh 4) in 31 patients. All of the patients with Marsh 1 on biopsy were diagnosed based on positive anti-TTG IgA and suggestive GI symptoms that improved on a gluten-free diet (GFD). In 1 patient with a family history of CD, positive endomysial antibodies, positive anti-TTG IgA (>100, normal <4 U/mL) and suggestive GI symptoms the SB biopsy was omitted. Her diagnosis was confirmed on the basis of symptom resolution and normalization of her serologic markers on GFD. ANOVA of vitamin concentration as a function of degree of atrophy showed no significant detectable difference between groups (F is <F crit and P > 0.05).
Vitamin Levels and Laboratory Results
Average vitamin E, 25 (OH) D, and vitamin A levels were 7.5 ± 2.0 mg/L, 32.8 ± 9.6 ng/mL, and 334.5 ± 109.9 μg/dL, respectively. No patients had vitamin A deficiency, and just 2 patients (2%) had vitamin E deficiency (<3.8 mg/L); both children had symptoms of poor weight gain and diarrhea. Neither patient had specific symptoms related to low vitamin E level. Both patients received multivitamin supplementation, and their vitamin E level was corrected after 3 to 4 months receiving GFD and vitamin supplement. Using the 2011 Institute of Medicine reported levels of vitamin D as a reference, 9 of 83 (11%) of our patients had mild to moderate deficiency (10–19 ng/mL), and no patients had severe deficiency (<10 ng/mL) (15). On the contrary, if we use the older definition, with vitamin D deficiency being <15 ng/mL, none of our patients would be vitamin D deficient (17). The 2 patients with vitamin E deficiency had ferritin levels of 9 and 22 μg/L and hemoglobin levels of 12.2 and 17.2 g/dL, respectively. In the 2 subjects with vitamin E deficiency, the deficiency was corrected by supplementation and the levels were normalized. On the contrary, 16 patients were anemic, with a hemoglobin level <12 g/dL (in these 16 patients, the median hemoglobin was 11.4 g/dL, with a range of 10.4–11.9 g/dL). A total of 74 of the 83 (89%) patients had their prothrombin time (PT) checked (an indirect way to measure vitamin K levels); average PT was 10.2 (range 8.4–12). Only 6 patients (8%) had mildly prolonged PT that PT, which was corrected after starting the GFD and gluten-free vitamin supplements.
ANOVA of vitamin concentration as a function of age was performed after dividing the cohort into >5 years and ≤5 years of age. In regard to vitamins D and E, there was no difference between groups. On the contrary, in terms of vitamin A, a difference existed in the levels between both age groups (F > F crit, P = 0.025). The median vitamin A level in the group >5 years was 332 μg/dL (range 45–653 μg/dL), whereas in the group ≤ 5 years of age, it was 289.5 μg/dL (range 189–474 μg/dL).
This study interestingly showed that fat-soluble vitamin deficiencies are uncommon in modern-era pediatric CD. This is consistent with the reports that suggested a change in CD presentation and introduce the new concept of nonmalabsorptive CD. It can also be attributed to the timely diagnosis of CD in our patient population. Prompt diagnosis may have allowed for early institution of GFD and prevented progression of disease to the malabsorptive type. Other possibilities include the routine use of vitamin supplements or fortification of cereal products with vitamins. None of our 83 pediatric patients with CD had vitamin A deficiency; only 2 patients had vitamin E deficiency and 9 patients had mild-to-moderate vitamin D deficiency. Both patients with vitamin E deficiency presented with typical GI malabsorptive symptoms of diarrhea, poor weight gain, and abdominal distention for a period of 3 months in 1 patient and 1 year in the other before diagnosis. Both patients had complete villous atrophy on endoscopic SB biopsy.
These findings agree with a study published by Villanueva et al (18) that demonstrated no significant difference in 25 (OH) D levels between children without CD and those with CD when this vitamin level was adjusted for BMI. In a study of 30 children and adolescents on a long-term GFD (mean of 10.7 years), their bone mineral density and serum markers of bone metabolism completely normalized (19). Moreover, 31 patients (37%) from our cohort had insufficient 25 (OH) D (15–29 ng/mL), much lower than the previously reported 61% of pediatric patients identified as 25 (OH) D insufficient in a 2001–2004 report of the US screening of the prevalence of 25 (OH) D deficiency in children (20).
Our findings of the uncommon incidence of fat-soluble vitamin deficiency in children with CD were maintained even in symptomatic patients with reported FTT or poor weight gain, in whom a low nutritional status may be expected.
Although literature from the adult population may support the presence of fat-soluble deficiency in CD (21–23), it is likely that the duration of the disease and the severity of mucosal injury could contribute to this discrepancy between adult and pediatric populations.
The strength of our study is that it is the first to our knowledge to assess the prevalence of fat-soluble vitamin deficiencies in children with CD. The limitations of our study include collection of data from a single tertiary center (Mayo Clinic) and the small sample size from which the data were analyzed.
It appears that age may play a role in the levels of vitamin A in patients with CD; this was reflected in our ANOVA analysis. A significantly higher median concentration of vitamin A was present in patients >5 years of age as compared with younger patients. Further investigation may be warranted to determine the underlying reason for lower vitamin A levels in the young patients with CD (≤5 years of age).
One weakness of our study was that not all children with newly diagnosed CD undergo vitamin level measurements, which may lead to potential bias; however, if such a clinical bias occurred, it is likely that it would overestimate the frequency of deficiencies because clinicians may be more likely to test for vitamin deficiencies in sicker patients.
Future directions for research include conducting a prospective multicenter trial to assess the true incidence of fat-soluble vitamin deficiency in various pediatric patients with CD. This in turn will help better define if checking fat-soluble vitamin levels as a part of routine assessment for pediatric patients with CD is needed or cost-effective.
In conclusion, fat-soluble vitamin deficiencies seem to be uncommon in our pediatric patients with CD, and the cases of mild deficiencies corrected with GFD and vitamins supplements. We conclude that routine measuring of fat-soluble vitamins levels may not be indicated. Despite having many diagnosis and management guidelines, there has been no agreement on what testing should be included in the assessment of a pediatric patient with newly diagnosed CD. For that, more studies may be needed to better define the necessary versus the excessive routine tests in this group of patients. Such studies may help reduce the financial burden on our health care system and minimize some distress posed by excessive testing on our patients.
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