TY - JOUR
AU - Cabrera, Jose, Mariano
AB - Abstract Background This systematic review critically analyzes the current research on micronutrient deficiency in children with inflammatory bowel disease (IBD) and synthesizes these data to provide evidence-based guidelines for nutritional surveillance in this population. Methods We searched 5 databases (Ovid Medline, PubMed, Scopus, CINAHL, and Cochrane Library) for studies evaluating micronutrients in patients with IBD using the following inclusion criteria: 1) original research, 2) published 1996 or later; 3) published in English; 4) human subjects; and 5) containing pediatric data. Studies were reviewed and included based on the strength of research methods. Data on the prevalence of micronutrient deficiencies in pediatric patients with IBD and risk factors for micronutrient deficiency in these patients were extracted from included studies and compared and discussed in preparation of the proposed guidelines and manuscript. Results A total of 39 studies were included in the final review. The data presented in these studies show that iron deficiency and vitamin D deficiency are common in pediatric patients with IBD. Vitamin B12 and folate deficiency are rare. Zinc deficiency, while not common, occurs at a higher rate in patients with Crohn’s disease than in healthy controls. There was limited data on vitamins A, E, and C, and selenium, but deficiency of these micronutrients seems rare. Conclusions We recommend annual surveillance of iron and vitamin D in pediatric patients with IBD regardless of disease activity or phenotype. Zinc should be monitored annually in patients with Crohn’s disease. There is insufficient evidence to support routine screening for other micronutrient deficiencies. pediatric nutrition, micronutrient deficiency, nutritional assessment, vitamin D deficiency, iron deficiency Inflammatory bowel disease (IBD) affects children worldwide, and its incidence is increasing throughout the world.1 As the population of children with IBD has grown, so too has the body of research addressing both therapeutic management and population health management, including quality of life and psychosocial impact of living with IBD,2 management of immunizations,3 and transition to adult care.4 One of the quickest growing areas of research within pediatric IBD has been nutrition. Nutritional status has been shown to be an important factor in the prognosis of IBD. Micronutrient deficiencies have also been shown to have important implications for outcomes. Patients with IBD who have anemia have a poorer quality of life and cognitive function.5 In addition, vitamin D deficiency has been associated with an increased risk of relapse6 and increased disease activity,7 whereas normalization of vitamin D levels has been associated with decreased risk of surgery.8 This evolving emphasis on micronutrient deficiencies in children with IBD has led to the incorporation of micronutrient status in published guidelines on the care of pediatric IBD. The North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHGAN) published guidelines in 2012 recommending “routine nutritional laboratory assessment in children with IBD”.9 European guidelines similarly recommend micronutrient laboratory evaluation in patients with IBD “on a regular basis… perhaps annually to screen for deficiency”.10 Most recently, the Porto IBD group of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESGPHAN) published a position paper on nutrition in IBD, including recommendations for screening for micronutrient deficiencies.11 They supported routine measurement of iron studies, vitamin D, folic acid, and vitamin B12 but did not recommend screening for zinc, selenium, or other micronutrients. Despite the agreement for nutritional surveillance in these different guidelines, there has not been consensus regarding how and when to screen for micronutrient deficiencies. The purpose of this systematic review is to critically analyze the current research on micronutrient deficiency in children with IBD and synthesize these data to provide evidence-based guidelines on nutritional surveillance in children with IBD. METHODS Our aims for this systematic review were to answer the following questions: 1) What micronutrient deficiencies are common in pediatric patients with IBD? 2) Which patients are at highest risk of micronutrient deficiencies? 3) Whom should providers screen? All patients or only those with certain risk factors? We searched 5 databases (Ovid Medline, PubMed, Scopus, CINAHL, and Cochrane Library) with the following inclusion criteria: 1) original research including systematic reviews and case reports, 2) published in 1996 or later; 3) published in English; 4) human subjects research; and 5) containing pediatric data. Search terms included Crohn’s disease, ulcerative colitis, and/or inflammatory bowel disease, nutrition assessment/nutritional status, and deficiency. We included the following micronutrients: folic acid, zinc, copper, selenium, iron/anemia, and vitamins A, B12, D, E, and K. The search strategy was developed in Ovid Medline (see Appendix A for full strategy) and was adapted appropriately for each database. From these results, (1553 abstracts), 2 authors (JF and CW) reviewed the titles and abstracts to confirm studies fit inclusion criteria. Studies with only abstracts published were excluded. Review articles within our search criteria had their bibliographies reviewed by 2 authors for additional articles potentially pertinent to our review. A final selection of 120 articles were then distributed to all authors for review such that each paper was reviewed by 2 authors using the Academy of Nutrition and Dietetic (AND) Evidence Analysis Process.12 Using the AND’s Quality Criteria Checklist for Primary Research, studies were rated positive, neutral, or negative based on their research methods and results. If the 2 reviewers did not agree on the rating, a third author reviewed and rated the study. Negative studies and studies which did not include data on patients younger than 16 years were excluded at this stage. Studies that only reported hemoglobin levels but not specific micronutrients were excluded from further study. Significant findings related to micronutrient deficiencies in children with IBD were extracted from all articles that met our inclusion criteria. These results were compared and discussed by the workgroup in preparation of the manuscript. RESULTS Our literature search identified 1533 studies. Screening for eligibility and study quality greatly reduced this number (Fig. 1). A total of 39 studies with 2903 subjects and 1115 controls were included in the final review. These studies were categorized based on the micronutrients assessed as listed in the following sections. FIGURE 1. View largeDownload slide Article selection and review process. FIGURE 1. View largeDownload slide Article selection and review process. Iron Twelve studies assessed iron indices (serum iron, ferritin, total iron binding capacity [TIBC], and transferrin saturation [%TS]) in patients with IBD (Table 1). Table 1: Summary Table of Studies Measuring Iron Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Ferritin <22ng/mL: 53% Berni 14 47 patients with new diagnosis of CD starting nutrition therapy or steroids (8–17 years) No controls Retrospective study Baseline iron level <40 mcg/dL for all groups. A significant increase in serum iron was seen after 8 weeks of treatment with enteral nutrition but not with steroids. Burpee 24 19 patients with CD from a single center (9–20 years) 10 controls Prospective study 11/19 subjects (58%) with CD had anemia compared with 2/10 controls (20%) Median serum iron (ug/dL) Median ferritin (ng/mL) Median TIBC (ug/dL) Anemic patients 39 59 287 Non-anemic patients 66 39 281 Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study ID (cut off values not defined): 20% of pts with inactive disease 8% of patients with active disease 5% of controls Serum ferritin levels lower in CD than controls Goodhand 20 59 consecutive patients (37 CD, 19 UC, 3 IC) (3–17 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 88% of children, 83% of adolescents Oustaman-olakis 21 49 consecutive patients at a GI center (51 CD, 49 UC) (15–79 years) 102 controls (19–61 years) Prospective study IDA: ferritin <30 mg/l and %TS <16% with anemia defined by WHO criteria 30% of patients had IDA Revel-Vilk 22 63 patients (50 CD, 13 UC) (9 to 22 years) 24 controls (9–14 years) Prospective study IDA (defined as serum ferritin <23 ug/l for males, <6 ug/l for females and MCV <77): 17.5% of patients had IDA Semrin 16 15 patients with CD (12–21 years) No controls Prospective study ID(serum iron <50 to 120 μg/L and TIBC >250 to 420 μg/dL) No difference in hemoglobin, serum iron or TIBC between active and inactive CD Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Hgb and serum iron were significantly lower in children with IBD compared with controls Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) No controls Prospective study ID based on serum iron (<50 ug/dL) was found in 77% ID based on %TS (<16%) was found in 72% Low ferritin (<100 ug/L) was noted in 69% of patients. Patients with PCDAI >30 more likely to have low iron and hemoglobin compared with PCDAI <30 Wiskin 19 80 patients (46 CD, 34 UC) (10–16 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 90% of children with CD and 95% of children with UC at diagnosis At follow up 2 years later, 70% of children with CD and 65% of children with UC were iron deficient. Dohil 17 4 patients with CD and anemia refractory to oral iron (2.6- 17 years) No controls At baseline, serum iron low in 4/4 patients, ferritin low in 3/4, %TS low in 4/4 patients. Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Ferritin <22ng/mL: 53% Berni 14 47 patients with new diagnosis of CD starting nutrition therapy or steroids (8–17 years) No controls Retrospective study Baseline iron level <40 mcg/dL for all groups. A significant increase in serum iron was seen after 8 weeks of treatment with enteral nutrition but not with steroids. Burpee 24 19 patients with CD from a single center (9–20 years) 10 controls Prospective study 11/19 subjects (58%) with CD had anemia compared with 2/10 controls (20%) Median serum iron (ug/dL) Median ferritin (ng/mL) Median TIBC (ug/dL) Anemic patients 39 59 287 Non-anemic patients 66 39 281 Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study ID (cut off values not defined): 20% of pts with inactive disease 8% of patients with active disease 5% of controls Serum ferritin levels lower in CD than controls Goodhand 20 59 consecutive patients (37 CD, 19 UC, 3 IC) (3–17 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 88% of children, 83% of adolescents Oustaman-olakis 21 49 consecutive patients at a GI center (51 CD, 49 UC) (15–79 years) 102 controls (19–61 years) Prospective study IDA: ferritin <30 mg/l and %TS <16% with anemia defined by WHO criteria 30% of patients had IDA Revel-Vilk 22 63 patients (50 CD, 13 UC) (9 to 22 years) 24 controls (9–14 years) Prospective study IDA (defined as serum ferritin <23 ug/l for males, <6 ug/l for females and MCV <77): 17.5% of patients had IDA Semrin 16 15 patients with CD (12–21 years) No controls Prospective study ID(serum iron <50 to 120 μg/L and TIBC >250 to 420 μg/dL) No difference in hemoglobin, serum iron or TIBC between active and inactive CD Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Hgb and serum iron were significantly lower in children with IBD compared with controls Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) No controls Prospective study ID based on serum iron (<50 ug/dL) was found in 77% ID based on %TS (<16%) was found in 72% Low ferritin (<100 ug/L) was noted in 69% of patients. Patients with PCDAI >30 more likely to have low iron and hemoglobin compared with PCDAI <30 Wiskin 19 80 patients (46 CD, 34 UC) (10–16 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 90% of children with CD and 95% of children with UC at diagnosis At follow up 2 years later, 70% of children with CD and 65% of children with UC were iron deficient. Dohil 17 4 patients with CD and anemia refractory to oral iron (2.6- 17 years) No controls At baseline, serum iron low in 4/4 patients, ferritin low in 3/4, %TS low in 4/4 patients. A comprehensive table reviewing these studies can be found in the supplementary material online. Legend: Hgb, hemoglobin; IC, indeterminate colitis; ID, iron deficiency; IDA, iron deficiency anemia; TI, terminal ileum. View Large Table 1: Summary Table of Studies Measuring Iron Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Ferritin <22ng/mL: 53% Berni 14 47 patients with new diagnosis of CD starting nutrition therapy or steroids (8–17 years) No controls Retrospective study Baseline iron level <40 mcg/dL for all groups. A significant increase in serum iron was seen after 8 weeks of treatment with enteral nutrition but not with steroids. Burpee 24 19 patients with CD from a single center (9–20 years) 10 controls Prospective study 11/19 subjects (58%) with CD had anemia compared with 2/10 controls (20%) Median serum iron (ug/dL) Median ferritin (ng/mL) Median TIBC (ug/dL) Anemic patients 39 59 287 Non-anemic patients 66 39 281 Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study ID (cut off values not defined): 20% of pts with inactive disease 8% of patients with active disease 5% of controls Serum ferritin levels lower in CD than controls Goodhand 20 59 consecutive patients (37 CD, 19 UC, 3 IC) (3–17 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 88% of children, 83% of adolescents Oustaman-olakis 21 49 consecutive patients at a GI center (51 CD, 49 UC) (15–79 years) 102 controls (19–61 years) Prospective study IDA: ferritin <30 mg/l and %TS <16% with anemia defined by WHO criteria 30% of patients had IDA Revel-Vilk 22 63 patients (50 CD, 13 UC) (9 to 22 years) 24 controls (9–14 years) Prospective study IDA (defined as serum ferritin <23 ug/l for males, <6 ug/l for females and MCV <77): 17.5% of patients had IDA Semrin 16 15 patients with CD (12–21 years) No controls Prospective study ID(serum iron <50 to 120 μg/L and TIBC >250 to 420 μg/dL) No difference in hemoglobin, serum iron or TIBC between active and inactive CD Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Hgb and serum iron were significantly lower in children with IBD compared with controls Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) No controls Prospective study ID based on serum iron (<50 ug/dL) was found in 77% ID based on %TS (<16%) was found in 72% Low ferritin (<100 ug/L) was noted in 69% of patients. Patients with PCDAI >30 more likely to have low iron and hemoglobin compared with PCDAI <30 Wiskin 19 80 patients (46 CD, 34 UC) (10–16 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 90% of children with CD and 95% of children with UC at diagnosis At follow up 2 years later, 70% of children with CD and 65% of children with UC were iron deficient. Dohil 17 4 patients with CD and anemia refractory to oral iron (2.6- 17 years) No controls At baseline, serum iron low in 4/4 patients, ferritin low in 3/4, %TS low in 4/4 patients. Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Ferritin <22ng/mL: 53% Berni 14 47 patients with new diagnosis of CD starting nutrition therapy or steroids (8–17 years) No controls Retrospective study Baseline iron level <40 mcg/dL for all groups. A significant increase in serum iron was seen after 8 weeks of treatment with enteral nutrition but not with steroids. Burpee 24 19 patients with CD from a single center (9–20 years) 10 controls Prospective study 11/19 subjects (58%) with CD had anemia compared with 2/10 controls (20%) Median serum iron (ug/dL) Median ferritin (ng/mL) Median TIBC (ug/dL) Anemic patients 39 59 287 Non-anemic patients 66 39 281 Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study ID (cut off values not defined): 20% of pts with inactive disease 8% of patients with active disease 5% of controls Serum ferritin levels lower in CD than controls Goodhand 20 59 consecutive patients (37 CD, 19 UC, 3 IC) (3–17 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 88% of children, 83% of adolescents Oustaman-olakis 21 49 consecutive patients at a GI center (51 CD, 49 UC) (15–79 years) 102 controls (19–61 years) Prospective study IDA: ferritin <30 mg/l and %TS <16% with anemia defined by WHO criteria 30% of patients had IDA Revel-Vilk 22 63 patients (50 CD, 13 UC) (9 to 22 years) 24 controls (9–14 years) Prospective study IDA (defined as serum ferritin <23 ug/l for males, <6 ug/l for females and MCV <77): 17.5% of patients had IDA Semrin 16 15 patients with CD (12–21 years) No controls Prospective study ID(serum iron <50 to 120 μg/L and TIBC >250 to 420 μg/dL) No difference in hemoglobin, serum iron or TIBC between active and inactive CD Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Hgb and serum iron were significantly lower in children with IBD compared with controls Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) No controls Prospective study ID based on serum iron (<50 ug/dL) was found in 77% ID based on %TS (<16%) was found in 72% Low ferritin (<100 ug/L) was noted in 69% of patients. Patients with PCDAI >30 more likely to have low iron and hemoglobin compared with PCDAI <30 Wiskin 19 80 patients (46 CD, 34 UC) (10–16 years) No controls Retrospective study ID (ferritin <30 ug/L when CRP was <10 mg/L, or ferritin <100 ug/L when CRP >10 mg/L and/or %TS <16%): 90% of children with CD and 95% of children with UC at diagnosis At follow up 2 years later, 70% of children with CD and 65% of children with UC were iron deficient. Dohil 17 4 patients with CD and anemia refractory to oral iron (2.6- 17 years) No controls At baseline, serum iron low in 4/4 patients, ferritin low in 3/4, %TS low in 4/4 patients. A comprehensive table reviewing these studies can be found in the supplementary material online. Legend: Hgb, hemoglobin; IC, indeterminate colitis; ID, iron deficiency; IDA, iron deficiency anemia; TI, terminal ileum. View Large Two studies reported iron indices in patients newly diagnosed with Crohn’s disease (CD). Song et al found that in patients with newly diagnosed CD, 77% had low serum iron, 72% had low %TS, and 69% had low serum ferritin.13 Berni et al reported the average baseline serum iron for newly diagnosed patients with CD, which was below the standard reference value.14 Three studies reported iron status in relation to disease activity and location in patients with CD. Song et al13 found that newly diagnosed patients with a Pediatric Crohn's Disease Activity Index (PCDAI) >30 were more likely to have low iron levels than patients with PCDAI <30. This group also found lower iron levels in patients with L3 (ileocolonic) disease compared with patients with L1 (ileal) or L2 (colonic). Costa reported that overall, 20% of patients with inactive disease had iron deficiency, compared with ~8% of patients with active disease and 5% of controls.15 This group also reported that serum ferritin levels were lower in patients in remission, although this was not statistically significant. Another study found that there was no difference in mean hemoglobin, serum iron, or TIBC between patients with active and inactive CD.16 Two studies reported the status of patients with CD receiving nutrition supplements (including iron). Dohil et al reviewed 4 patients with anemia refractory to oral iron therapy.17 In this cohort, all patients had low serum iron and %TS, and 75% of patients had low ferritin, despite prior treatment of at least 3–6 mg/kg per day of elemental iron. Berni et al found that 8 weeks of nutrition therapy was more effective than steroids in improving serum iron levels.14 Six studies reporting the prevalence of low iron indices included both patients with CD and ulcerative colitis (UC). Two of these studies looked at iron status for newly diagnosed patients. Sikora et al reported that patients with newly diagnosed IBD were significantly more likely to have low serum iron compared with healthy controls.18 Wiskin et al noted that 90% of patients with CD and 95% of patients with UC were iron deficient at diagnosis.19 Seventy percent of patients with CD and 65% of patients with UC were iron deficient at 2-year follow-up. Goodhand et al measured iron indices on consecutive clinic patients with IBD and found that 88% of children and 83% of adolescents had iron-deficiency anemia.20 Oustamanolakis analyzed 100 patients with CD in Greece and found that 30% of patients had iron deficiency anemia.21 In this study, patients with CD had lower serum ferritin and %TS and higher soluble transferrin receptor (sTfR) than patients with UC and controls. Revel-Vilk et al investigated 63 patients with CD and UC and found that 17% had iron-deficiency anemia.22 Hartman et al found that 53% of consecutive patients recruited from an outpatient clinic had low serum ferritin; 20% of these patients were on iron supplements23, 24 Vitamin B12 Eight studies investigated vitamin B12 status in children with IBD (Table 2). All of these studies measured serum vitamin B12, and none included methylmalonic acid (MMA) or homocysteine levels, which are considered helpful in defining functional B12 deficiency, as normal serum levels of B12 are poorly defined. Four studies17, 18, 20, 25 (combined n = 278) found no patients with low vitamin B12 status. These studies included patients with CD and UC, including patients with ileal disease. Only one of these studies excluded patients taking nutritional supplements.18 Two studies found 1 CD patient each (combined n = 139) with low serum B12 level, although their normal levels differed.13, 23 Costa et al in Brazil found that 20% of patients with inactive CD had low serum B12 values, compared with <5% of patients with active disease and 5%–10% of healthy controls.15 The reference values used for vitamin B12 and additional disease characteristics of these patients were not described. Yakut et al found that 22.2% of patients with CD and 7.5% of patients with UC had low vitamin B12 status.26 They also reported that patients with ileal or ileocolonic resection were more likely to have abnormal serum vitamin B12 concentrations, but they found no difference in serum vitamin B12 concentrations based on sex, age, disease duration, disease location, or prevalence of anemia. Table 2: Summary Table of Studies Measuring Vitamin B12 and Folate Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Low vitamin B12 levels =2% (n=1) Low folate levels = 2% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study No patients with low vitamin B12 or folate levels Costa 15 51 patients with CD from single outpatient clinic (13.2–19.4 years) 35 age-matched controls Prospective study Low vitamin B12 levels: ~20% with inactive disease, <5% with active disease and ~5%–10% of controls No patients with low folate levels Goodhand 20 59 patients (3–17 years) (37 CD, 19 UC, 3 IC) No controls Retrospective study No patients with low vitamin B12 or folate levels Heyman 27 37 IBD from 8 outpatient clinics across the USA (22 CD, 11 UC, 4 IC) (12.8 ± 2.7 years) 41 controls (11.4 ± 3.2 years) Prospective study No patients with low folate levels Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study No patients with low vitamin B12 or folate levels Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Low vitamin B12 levels =2% Low folate levels = 40%? Patients with moderate to severe disease more likely to have low folate Yakut 26 138 Patients (45 CD, 93 UC) (age not specified, 0–29) 53 Controls Retrospective study Low vitamin B12 levels in 22.2% of patients with CD, 7.5% of patients with UC Low folate levels = 28.8% of patients with CD, 8.6% of patients with UC Prior ileal disease or ileal resection were more likely to have vitamin B12 deficiency In CD patients, ileal disease was only risk factor for having a low folate level Dohil 17 4 patients with CD with anemia of chronic disease refractory to oral iron therapy (2.6–17 years) No patients with low vitamin B12 or folate levels Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Low vitamin B12 levels =2% (n=1) Low folate levels = 2% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study No patients with low vitamin B12 or folate levels Costa 15 51 patients with CD from single outpatient clinic (13.2–19.4 years) 35 age-matched controls Prospective study Low vitamin B12 levels: ~20% with inactive disease, <5% with active disease and ~5%–10% of controls No patients with low folate levels Goodhand 20 59 patients (3–17 years) (37 CD, 19 UC, 3 IC) No controls Retrospective study No patients with low vitamin B12 or folate levels Heyman 27 37 IBD from 8 outpatient clinics across the USA (22 CD, 11 UC, 4 IC) (12.8 ± 2.7 years) 41 controls (11.4 ± 3.2 years) Prospective study No patients with low folate levels Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study No patients with low vitamin B12 or folate levels Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Low vitamin B12 levels =2% Low folate levels = 40%? Patients with moderate to severe disease more likely to have low folate Yakut 26 138 Patients (45 CD, 93 UC) (age not specified, 0–29) 53 Controls Retrospective study Low vitamin B12 levels in 22.2% of patients with CD, 7.5% of patients with UC Low folate levels = 28.8% of patients with CD, 8.6% of patients with UC Prior ileal disease or ileal resection were more likely to have vitamin B12 deficiency In CD patients, ileal disease was only risk factor for having a low folate level Dohil 17 4 patients with CD with anemia of chronic disease refractory to oral iron therapy (2.6–17 years) No patients with low vitamin B12 or folate levels A comprehensive table reviewing these studies can be found in the supplementary material online. View Large Table 2: Summary Table of Studies Measuring Vitamin B12 and Folate Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Low vitamin B12 levels =2% (n=1) Low folate levels = 2% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study No patients with low vitamin B12 or folate levels Costa 15 51 patients with CD from single outpatient clinic (13.2–19.4 years) 35 age-matched controls Prospective study Low vitamin B12 levels: ~20% with inactive disease, <5% with active disease and ~5%–10% of controls No patients with low folate levels Goodhand 20 59 patients (3–17 years) (37 CD, 19 UC, 3 IC) No controls Retrospective study No patients with low vitamin B12 or folate levels Heyman 27 37 IBD from 8 outpatient clinics across the USA (22 CD, 11 UC, 4 IC) (12.8 ± 2.7 years) 41 controls (11.4 ± 3.2 years) Prospective study No patients with low folate levels Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study No patients with low vitamin B12 or folate levels Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Low vitamin B12 levels =2% Low folate levels = 40%? Patients with moderate to severe disease more likely to have low folate Yakut 26 138 Patients (45 CD, 93 UC) (age not specified, 0–29) 53 Controls Retrospective study Low vitamin B12 levels in 22.2% of patients with CD, 7.5% of patients with UC Low folate levels = 28.8% of patients with CD, 8.6% of patients with UC Prior ileal disease or ileal resection were more likely to have vitamin B12 deficiency In CD patients, ileal disease was only risk factor for having a low folate level Dohil 17 4 patients with CD with anemia of chronic disease refractory to oral iron therapy (2.6–17 years) No patients with low vitamin B12 or folate levels Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Low vitamin B12 levels =2% (n=1) Low folate levels = 2% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study No patients with low vitamin B12 or folate levels Costa 15 51 patients with CD from single outpatient clinic (13.2–19.4 years) 35 age-matched controls Prospective study Low vitamin B12 levels: ~20% with inactive disease, <5% with active disease and ~5%–10% of controls No patients with low folate levels Goodhand 20 59 patients (3–17 years) (37 CD, 19 UC, 3 IC) No controls Retrospective study No patients with low vitamin B12 or folate levels Heyman 27 37 IBD from 8 outpatient clinics across the USA (22 CD, 11 UC, 4 IC) (12.8 ± 2.7 years) 41 controls (11.4 ± 3.2 years) Prospective study No patients with low folate levels Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study No patients with low vitamin B12 or folate levels Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Low vitamin B12 levels =2% Low folate levels = 40%? Patients with moderate to severe disease more likely to have low folate Yakut 26 138 Patients (45 CD, 93 UC) (age not specified, 0–29) 53 Controls Retrospective study Low vitamin B12 levels in 22.2% of patients with CD, 7.5% of patients with UC Low folate levels = 28.8% of patients with CD, 8.6% of patients with UC Prior ileal disease or ileal resection were more likely to have vitamin B12 deficiency In CD patients, ileal disease was only risk factor for having a low folate level Dohil 17 4 patients with CD with anemia of chronic disease refractory to oral iron therapy (2.6–17 years) No patients with low vitamin B12 or folate levels A comprehensive table reviewing these studies can be found in the supplementary material online. View Large Folate Nine studies measured red blood cell (RBC) folate (Table 2). Six studies found no patients with low serum RBC folate.15, 17, 18, 20, 25, 27 These studies included patients with CD and UC, males and females, and patients with a variety of disease locations. Hartman et al found 1 patient (2%) from an outpatient clinic with low RBC folate.23 Song et al measured RBC folate in 71 patients in South Korea with newly diagnosed CD and found that 40% had low RBC folate (<5 ng/mL).13 Similarly, Yakut et al found low serum folate concentrations in 28.8% of patients with CD and 8.6% of patients with UC in Ankara, Turkey.26 In these patients, CD affecting the ileum was a risk factor for having a low folate level. Vitamin D The cutoff values for defining vitamin D deficiency have changed over time and often vary by institution.28, 29 For the purpose of our review, we defined vitamin D deficiency as 25-hydroxyvitaminD (25[OH]D) less than 20 ng/mL (50 nmol/L) and vitamin D insufficiency as 25(OH)D between 21 and 29 ng/mL (52.5–72.5 nmol/L).30 Twenty-one studies assessed vitamin D status using 25(OH)D (Table 3). Eight studies reviewed vitamin D status for patients with CD. Wingate et al (Canada) reviewed 83 patients with quiescent CD and found that 33% were vitamin D deficient and 79% were either insufficient or deficient; 31% of their patients were taking a vitamin D supplement at the time of the assessment.31 Similarly, Augustine et al (northern USA) reviewed vitamin D status of 87 patients with CD and found that 36% had vitamin D deficiency; 74% of patients were taking a vitamin D supplement with an average of 462 IU/day.32 Middleton et al (southern USA) found that 98% of African-American patients with CD and 83% of Caucasian patients with CD had vitamin D deficiency or insufficiency.33 In contrast, Costa et al (Brazil) found that none of the 51 patients with CD reviewed had low serum vitamin D, but the laboratory cutoff values were not described.15 Table 3: Summary Table of Studies Measuring Vitamin D Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Wingate 31 Initial = 83 patients with quiescent CD, 69 completed 6-month follow-up (14.3 +/- 2.3 years) No controls Prospective study 25(OH)D <16 ng/mL (40 nmol/L) = 16% 25(OH)D <20 ng/mL (<50 nmoL/L) = 33%25(OH)D <30 ng/mL (<75 nmoL/L) = 79% Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Deficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 25% of patients with IBD Insufficiency = 25(OH)D 20–31.9 ng/mL (50–79.8 nmol/L) = 55% of patients with IBD Thearle 58 1 patient (12 years) No controls Case study 25(OH)D <17 ng/mL (42.4 nmol/L) = 0% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study 25(OH)D <12 ng/mL (<30 nmol/L) = 62% of patients with IBD, 75% of controls Augustine 32 87 patients with CD (5–40 years) No controls Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) = 36% Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study 25 (OH) D <reference (value not defined) = 0% active CD, 0% inactive CD, 0% controls Cowan 36 32 patients from a single outpatient clinic (21 CD, 11 UC) (14.8 +/- 2.8 years) 58 controls 25(OH) D <8.0 ng/mL (<20 nmol/L) = 0% of patients with IBD Gokhale 37 99 consecutive patients (58 CD, 37 UC, 4 IC (14.1 +/- 3.1 years) 63 sibling controls Prospective study 25(OH)D <10 ng/mL (<25 nmol/L) = 0% of patients with IBD Laasko 34 47 patients (17 CD, 30 UC) (10.7–25.0 years) No controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 7% of patients with IBD Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 26% of patients with IBD Laasko 35 80 consecutive patients (26 CD, 51 UC, 3 IC) (5.1–20.1 years) 80 controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 30% of patients, 37% of controls Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 51% of patients with IBD Levin 39 78 patients (70 CD, 5 UC, 3 IC) (12.6 +/- 3.5 years) No controls Retrospective study Deficiency = 25(OH) D <20.4 ng/mL (<51 mmol/L) = 19.2% Moderate deficiency = 25(OH)D <20.4 ng/mL (<51 mmol/L) = 15.4% Severe deficiency = 25(OH)D <12 ng/mL (<30 nmol/L) = 3.8% Insufficiency = 25(OH)D 20.4–30 ng/mL (51–75 nmol/L) = 38% Middleton 33 116 CD patients (African American = 9–21 years, white = 8–21 years) 40 African-American controls (1–21 years) Cross-sectional study Deficiency = 25(OH) D <15 ng/mL (<37.5 nmol/L) = 63% of African- American patients, 32% of white patients, 70% of controls Insufficiency = 25(OH)D <32 ng/mL (<80 nmol/L) = 98% of African- American patients, 83% of white patients, 98% of controls African-American race (P <0.001) and male sex (P = 0.002) to be significant predictors of lower serum 25OHD concentration. Pappa 41 130 patients (94 CD, 36 UC) (15 +/- 3 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 34.6% of patients with IBD, 38.3% of patients with CD, 25% of patients with UC Severe deficiency = 25(OH)D <8 ng/mL (<20 nmol/L) = 10.8% of patients with IBD, 12.8% of patients with CD, 5.7% of patients with UC Pappa 42 448 patients (288 CD, 143 UC, 17 IC) (15.7 +/- 3.2 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 5.8% of patients, 4.2% % of patients with CD, 8.4% of patients with UC 14.3% (CD 10.8, UC 19.6) (p=0.01) 58.5% (CD 55.6; UC 63.6) (p=0.1) Pappa 59 63 patients (37 CD, 26 UC) with 25(OH) D >20 ng/ mL at enrollment (14.8 +/- 3.1 years) randomized to 3 vitamin D supplementation regimens with 4 follow up visits No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) at all 4 follow-up visits = 82.4% Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) at all 4 follow-up visits = 23.5% Weekly outdoors exposure and supplemental daily vitamin D intake were predictive of higher vitamin D levels. Pappa 60 71 patients (42 CD, 27 UC, 3 IC) with 25(OH)D <20ng/mL at enrollment (5–21 yr) randominzed to 3 vitamin D supplementation regimens No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) = 75% of group A, 62% of group B, 25% of group C Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) = 25% of group A, 5% of group B, 5% of group C Prosnitz 44 78 patients with CD, 52 completed follow-up (12.7 +/- 2.8 years) 221 controls(13.5 +/- 4.4 years) Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) at diagnosis = 100% of African- American patients, 36% of white patients, 42% of all patients with CD, 69% of African-American Controls, 26% of white controls At final visit, 3% of CD patients were deficient Lower baseline PCDAI and lower baseline 25(OH)D levels were associated with greater increases in 25(OH)D over time. Sentongo 43 112 CD patients from a single center (16.2 +/- 4.1 years) No controls Cross-sectional study 25(OH)D <15.2 ng/mL (<38 nmol/L) = 16% of patients with CD, 56% of African-American patients, 13% of white patients Relative risk of hypovitaminosis D among African Americans was 4.23 Szabo 47 50 patients with CD on infliximab (14.8 +/- 2.4 years) 34 controls (patients with CD not on infliximab) Prospective cohort Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 57.4% of infliximab group, 25% of controls at baseline, 40.0% of infliximab group at 1 year Veit 45 59 patients (40 CD, 19 UC) (16.4 +/- 2.2 years) 116 controls (14.6 +/- 4.4 years) Retrospective review Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 42.4% of patients with IBD; 26.7% of controls Insufficiency = 25 (OH)D 20–29.9 ng/mL (50–74 nmol/L) = 18.6% of patients with IBD; 10.3% of controls Patients with UC had a non-significantly higher prevalence of vitamin D deficiency compared with the CD participants (50% versus 40%; P = 0.53) Walther 46 90 patients (56 CD, 30 UC, 4 IC) (14.4 +/- 2.2 years) 52 controls (12.9 +/- 3.0 years) 25(OH)D <lower range of normal (not defined) = 29% of steroid-naïve patients, 20% of steroid-treated patients Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Wingate 31 Initial = 83 patients with quiescent CD, 69 completed 6-month follow-up (14.3 +/- 2.3 years) No controls Prospective study 25(OH)D <16 ng/mL (40 nmol/L) = 16% 25(OH)D <20 ng/mL (<50 nmoL/L) = 33%25(OH)D <30 ng/mL (<75 nmoL/L) = 79% Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Deficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 25% of patients with IBD Insufficiency = 25(OH)D 20–31.9 ng/mL (50–79.8 nmol/L) = 55% of patients with IBD Thearle 58 1 patient (12 years) No controls Case study 25(OH)D <17 ng/mL (42.4 nmol/L) = 0% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study 25(OH)D <12 ng/mL (<30 nmol/L) = 62% of patients with IBD, 75% of controls Augustine 32 87 patients with CD (5–40 years) No controls Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) = 36% Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study 25 (OH) D <reference (value not defined) = 0% active CD, 0% inactive CD, 0% controls Cowan 36 32 patients from a single outpatient clinic (21 CD, 11 UC) (14.8 +/- 2.8 years) 58 controls 25(OH) D <8.0 ng/mL (<20 nmol/L) = 0% of patients with IBD Gokhale 37 99 consecutive patients (58 CD, 37 UC, 4 IC (14.1 +/- 3.1 years) 63 sibling controls Prospective study 25(OH)D <10 ng/mL (<25 nmol/L) = 0% of patients with IBD Laasko 34 47 patients (17 CD, 30 UC) (10.7–25.0 years) No controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 7% of patients with IBD Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 26% of patients with IBD Laasko 35 80 consecutive patients (26 CD, 51 UC, 3 IC) (5.1–20.1 years) 80 controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 30% of patients, 37% of controls Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 51% of patients with IBD Levin 39 78 patients (70 CD, 5 UC, 3 IC) (12.6 +/- 3.5 years) No controls Retrospective study Deficiency = 25(OH) D <20.4 ng/mL (<51 mmol/L) = 19.2% Moderate deficiency = 25(OH)D <20.4 ng/mL (<51 mmol/L) = 15.4% Severe deficiency = 25(OH)D <12 ng/mL (<30 nmol/L) = 3.8% Insufficiency = 25(OH)D 20.4–30 ng/mL (51–75 nmol/L) = 38% Middleton 33 116 CD patients (African American = 9–21 years, white = 8–21 years) 40 African-American controls (1–21 years) Cross-sectional study Deficiency = 25(OH) D <15 ng/mL (<37.5 nmol/L) = 63% of African- American patients, 32% of white patients, 70% of controls Insufficiency = 25(OH)D <32 ng/mL (<80 nmol/L) = 98% of African- American patients, 83% of white patients, 98% of controls African-American race (P <0.001) and male sex (P = 0.002) to be significant predictors of lower serum 25OHD concentration. Pappa 41 130 patients (94 CD, 36 UC) (15 +/- 3 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 34.6% of patients with IBD, 38.3% of patients with CD, 25% of patients with UC Severe deficiency = 25(OH)D <8 ng/mL (<20 nmol/L) = 10.8% of patients with IBD, 12.8% of patients with CD, 5.7% of patients with UC Pappa 42 448 patients (288 CD, 143 UC, 17 IC) (15.7 +/- 3.2 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 5.8% of patients, 4.2% % of patients with CD, 8.4% of patients with UC 14.3% (CD 10.8, UC 19.6) (p=0.01) 58.5% (CD 55.6; UC 63.6) (p=0.1) Pappa 59 63 patients (37 CD, 26 UC) with 25(OH) D >20 ng/ mL at enrollment (14.8 +/- 3.1 years) randomized to 3 vitamin D supplementation regimens with 4 follow up visits No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) at all 4 follow-up visits = 82.4% Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) at all 4 follow-up visits = 23.5% Weekly outdoors exposure and supplemental daily vitamin D intake were predictive of higher vitamin D levels. Pappa 60 71 patients (42 CD, 27 UC, 3 IC) with 25(OH)D <20ng/mL at enrollment (5–21 yr) randominzed to 3 vitamin D supplementation regimens No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) = 75% of group A, 62% of group B, 25% of group C Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) = 25% of group A, 5% of group B, 5% of group C Prosnitz 44 78 patients with CD, 52 completed follow-up (12.7 +/- 2.8 years) 221 controls(13.5 +/- 4.4 years) Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) at diagnosis = 100% of African- American patients, 36% of white patients, 42% of all patients with CD, 69% of African-American Controls, 26% of white controls At final visit, 3% of CD patients were deficient Lower baseline PCDAI and lower baseline 25(OH)D levels were associated with greater increases in 25(OH)D over time. Sentongo 43 112 CD patients from a single center (16.2 +/- 4.1 years) No controls Cross-sectional study 25(OH)D <15.2 ng/mL (<38 nmol/L) = 16% of patients with CD, 56% of African-American patients, 13% of white patients Relative risk of hypovitaminosis D among African Americans was 4.23 Szabo 47 50 patients with CD on infliximab (14.8 +/- 2.4 years) 34 controls (patients with CD not on infliximab) Prospective cohort Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 57.4% of infliximab group, 25% of controls at baseline, 40.0% of infliximab group at 1 year Veit 45 59 patients (40 CD, 19 UC) (16.4 +/- 2.2 years) 116 controls (14.6 +/- 4.4 years) Retrospective review Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 42.4% of patients with IBD; 26.7% of controls Insufficiency = 25 (OH)D 20–29.9 ng/mL (50–74 nmol/L) = 18.6% of patients with IBD; 10.3% of controls Patients with UC had a non-significantly higher prevalence of vitamin D deficiency compared with the CD participants (50% versus 40%; P = 0.53) Walther 46 90 patients (56 CD, 30 UC, 4 IC) (14.4 +/- 2.2 years) 52 controls (12.9 +/- 3.0 years) 25(OH)D <lower range of normal (not defined) = 29% of steroid-naïve patients, 20% of steroid-treated patients A comprehensive table reviewing these studies can be found in the supplementary material. Legend: IBDU: Inflammatory bowel disease unclassified; IC: indeterminate colitis; TI: terminal ileum. View Large Table 3: Summary Table of Studies Measuring Vitamin D Status Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Wingate 31 Initial = 83 patients with quiescent CD, 69 completed 6-month follow-up (14.3 +/- 2.3 years) No controls Prospective study 25(OH)D <16 ng/mL (40 nmol/L) = 16% 25(OH)D <20 ng/mL (<50 nmoL/L) = 33%25(OH)D <30 ng/mL (<75 nmoL/L) = 79% Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Deficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 25% of patients with IBD Insufficiency = 25(OH)D 20–31.9 ng/mL (50–79.8 nmol/L) = 55% of patients with IBD Thearle 58 1 patient (12 years) No controls Case study 25(OH)D <17 ng/mL (42.4 nmol/L) = 0% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study 25(OH)D <12 ng/mL (<30 nmol/L) = 62% of patients with IBD, 75% of controls Augustine 32 87 patients with CD (5–40 years) No controls Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) = 36% Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study 25 (OH) D <reference (value not defined) = 0% active CD, 0% inactive CD, 0% controls Cowan 36 32 patients from a single outpatient clinic (21 CD, 11 UC) (14.8 +/- 2.8 years) 58 controls 25(OH) D <8.0 ng/mL (<20 nmol/L) = 0% of patients with IBD Gokhale 37 99 consecutive patients (58 CD, 37 UC, 4 IC (14.1 +/- 3.1 years) 63 sibling controls Prospective study 25(OH)D <10 ng/mL (<25 nmol/L) = 0% of patients with IBD Laasko 34 47 patients (17 CD, 30 UC) (10.7–25.0 years) No controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 7% of patients with IBD Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 26% of patients with IBD Laasko 35 80 consecutive patients (26 CD, 51 UC, 3 IC) (5.1–20.1 years) 80 controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 30% of patients, 37% of controls Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 51% of patients with IBD Levin 39 78 patients (70 CD, 5 UC, 3 IC) (12.6 +/- 3.5 years) No controls Retrospective study Deficiency = 25(OH) D <20.4 ng/mL (<51 mmol/L) = 19.2% Moderate deficiency = 25(OH)D <20.4 ng/mL (<51 mmol/L) = 15.4% Severe deficiency = 25(OH)D <12 ng/mL (<30 nmol/L) = 3.8% Insufficiency = 25(OH)D 20.4–30 ng/mL (51–75 nmol/L) = 38% Middleton 33 116 CD patients (African American = 9–21 years, white = 8–21 years) 40 African-American controls (1–21 years) Cross-sectional study Deficiency = 25(OH) D <15 ng/mL (<37.5 nmol/L) = 63% of African- American patients, 32% of white patients, 70% of controls Insufficiency = 25(OH)D <32 ng/mL (<80 nmol/L) = 98% of African- American patients, 83% of white patients, 98% of controls African-American race (P <0.001) and male sex (P = 0.002) to be significant predictors of lower serum 25OHD concentration. Pappa 41 130 patients (94 CD, 36 UC) (15 +/- 3 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 34.6% of patients with IBD, 38.3% of patients with CD, 25% of patients with UC Severe deficiency = 25(OH)D <8 ng/mL (<20 nmol/L) = 10.8% of patients with IBD, 12.8% of patients with CD, 5.7% of patients with UC Pappa 42 448 patients (288 CD, 143 UC, 17 IC) (15.7 +/- 3.2 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 5.8% of patients, 4.2% % of patients with CD, 8.4% of patients with UC 14.3% (CD 10.8, UC 19.6) (p=0.01) 58.5% (CD 55.6; UC 63.6) (p=0.1) Pappa 59 63 patients (37 CD, 26 UC) with 25(OH) D >20 ng/ mL at enrollment (14.8 +/- 3.1 years) randomized to 3 vitamin D supplementation regimens with 4 follow up visits No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) at all 4 follow-up visits = 82.4% Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) at all 4 follow-up visits = 23.5% Weekly outdoors exposure and supplemental daily vitamin D intake were predictive of higher vitamin D levels. Pappa 60 71 patients (42 CD, 27 UC, 3 IC) with 25(OH)D <20ng/mL at enrollment (5–21 yr) randominzed to 3 vitamin D supplementation regimens No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) = 75% of group A, 62% of group B, 25% of group C Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) = 25% of group A, 5% of group B, 5% of group C Prosnitz 44 78 patients with CD, 52 completed follow-up (12.7 +/- 2.8 years) 221 controls(13.5 +/- 4.4 years) Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) at diagnosis = 100% of African- American patients, 36% of white patients, 42% of all patients with CD, 69% of African-American Controls, 26% of white controls At final visit, 3% of CD patients were deficient Lower baseline PCDAI and lower baseline 25(OH)D levels were associated with greater increases in 25(OH)D over time. Sentongo 43 112 CD patients from a single center (16.2 +/- 4.1 years) No controls Cross-sectional study 25(OH)D <15.2 ng/mL (<38 nmol/L) = 16% of patients with CD, 56% of African-American patients, 13% of white patients Relative risk of hypovitaminosis D among African Americans was 4.23 Szabo 47 50 patients with CD on infliximab (14.8 +/- 2.4 years) 34 controls (patients with CD not on infliximab) Prospective cohort Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 57.4% of infliximab group, 25% of controls at baseline, 40.0% of infliximab group at 1 year Veit 45 59 patients (40 CD, 19 UC) (16.4 +/- 2.2 years) 116 controls (14.6 +/- 4.4 years) Retrospective review Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 42.4% of patients with IBD; 26.7% of controls Insufficiency = 25 (OH)D 20–29.9 ng/mL (50–74 nmol/L) = 18.6% of patients with IBD; 10.3% of controls Patients with UC had a non-significantly higher prevalence of vitamin D deficiency compared with the CD participants (50% versus 40%; P = 0.53) Walther 46 90 patients (56 CD, 30 UC, 4 IC) (14.4 +/- 2.2 years) 52 controls (12.9 +/- 3.0 years) 25(OH)D <lower range of normal (not defined) = 29% of steroid-naïve patients, 20% of steroid-treated patients Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Wingate 31 Initial = 83 patients with quiescent CD, 69 completed 6-month follow-up (14.3 +/- 2.3 years) No controls Prospective study 25(OH)D <16 ng/mL (40 nmol/L) = 16% 25(OH)D <20 ng/mL (<50 nmoL/L) = 33%25(OH)D <30 ng/mL (<75 nmoL/L) = 79% Hartman 23 68 consecutive patients (57 CD; 11 UC) (13.9 +/- 3.2 years) No controls Prospective study Deficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 25% of patients with IBD Insufficiency = 25(OH)D 20–31.9 ng/mL (50–79.8 nmol/L) = 55% of patients with IBD Thearle 58 1 patient (12 years) No controls Case study 25(OH)D <17 ng/mL (42.4 nmol/L) = 0% Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study 25(OH)D <12 ng/mL (<30 nmol/L) = 62% of patients with IBD, 75% of controls Augustine 32 87 patients with CD (5–40 years) No controls Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) = 36% Costa 15 51 patients with CD from a single outpatient clinic (13.2–19.4 years) 35 controls Prospective study 25 (OH) D <reference (value not defined) = 0% active CD, 0% inactive CD, 0% controls Cowan 36 32 patients from a single outpatient clinic (21 CD, 11 UC) (14.8 +/- 2.8 years) 58 controls 25(OH) D <8.0 ng/mL (<20 nmol/L) = 0% of patients with IBD Gokhale 37 99 consecutive patients (58 CD, 37 UC, 4 IC (14.1 +/- 3.1 years) 63 sibling controls Prospective study 25(OH)D <10 ng/mL (<25 nmol/L) = 0% of patients with IBD Laasko 34 47 patients (17 CD, 30 UC) (10.7–25.0 years) No controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 7% of patients with IBD Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 26% of patients with IBD Laasko 35 80 consecutive patients (26 CD, 51 UC, 3 IC) (5.1–20.1 years) 80 controls Prospective study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 30% of patients, 37% of controls Insufficiency = 25(OH)D <20 ng/mL (<50 nmol/L) = 51% of patients with IBD Levin 39 78 patients (70 CD, 5 UC, 3 IC) (12.6 +/- 3.5 years) No controls Retrospective study Deficiency = 25(OH) D <20.4 ng/mL (<51 mmol/L) = 19.2% Moderate deficiency = 25(OH)D <20.4 ng/mL (<51 mmol/L) = 15.4% Severe deficiency = 25(OH)D <12 ng/mL (<30 nmol/L) = 3.8% Insufficiency = 25(OH)D 20.4–30 ng/mL (51–75 nmol/L) = 38% Middleton 33 116 CD patients (African American = 9–21 years, white = 8–21 years) 40 African-American controls (1–21 years) Cross-sectional study Deficiency = 25(OH) D <15 ng/mL (<37.5 nmol/L) = 63% of African- American patients, 32% of white patients, 70% of controls Insufficiency = 25(OH)D <32 ng/mL (<80 nmol/L) = 98% of African- American patients, 83% of white patients, 98% of controls African-American race (P <0.001) and male sex (P = 0.002) to be significant predictors of lower serum 25OHD concentration. Pappa 41 130 patients (94 CD, 36 UC) (15 +/- 3 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 34.6% of patients with IBD, 38.3% of patients with CD, 25% of patients with UC Severe deficiency = 25(OH)D <8 ng/mL (<20 nmol/L) = 10.8% of patients with IBD, 12.8% of patients with CD, 5.7% of patients with UC Pappa 42 448 patients (288 CD, 143 UC, 17 IC) (15.7 +/- 3.2 years) No controls Cross-sectional study Deficiency = 25(OH)D <15 ng/mL (<37.5 nmol/L) = 5.8% of patients, 4.2% % of patients with CD, 8.4% of patients with UC 14.3% (CD 10.8, UC 19.6) (p=0.01) 58.5% (CD 55.6; UC 63.6) (p=0.1) Pappa 59 63 patients (37 CD, 26 UC) with 25(OH) D >20 ng/ mL at enrollment (14.8 +/- 3.1 years) randomized to 3 vitamin D supplementation regimens with 4 follow up visits No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) at all 4 follow-up visits = 82.4% Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) at all 4 follow-up visits = 23.5% Weekly outdoors exposure and supplemental daily vitamin D intake were predictive of higher vitamin D levels. Pappa 60 71 patients (42 CD, 27 UC, 3 IC) with 25(OH)D <20ng/mL at enrollment (5–21 yr) randominzed to 3 vitamin D supplementation regimens No controls Prospective study Suboptimal = 25(OH)D <32ng/mL (<80 nmol/L) = 75% of group A, 62% of group B, 25% of group C Deficient = 25 (OH)D <20ng/mL (<50 nmol/L) = 25% of group A, 5% of group B, 5% of group C Prosnitz 44 78 patients with CD, 52 completed follow-up (12.7 +/- 2.8 years) 221 controls(13.5 +/- 4.4 years) Prospective study 25(OH)D <20 ng/mL (<50 nmol/L) at diagnosis = 100% of African- American patients, 36% of white patients, 42% of all patients with CD, 69% of African-American Controls, 26% of white controls At final visit, 3% of CD patients were deficient Lower baseline PCDAI and lower baseline 25(OH)D levels were associated with greater increases in 25(OH)D over time. Sentongo 43 112 CD patients from a single center (16.2 +/- 4.1 years) No controls Cross-sectional study 25(OH)D <15.2 ng/mL (<38 nmol/L) = 16% of patients with CD, 56% of African-American patients, 13% of white patients Relative risk of hypovitaminosis D among African Americans was 4.23 Szabo 47 50 patients with CD on infliximab (14.8 +/- 2.4 years) 34 controls (patients with CD not on infliximab) Prospective cohort Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 57.4% of infliximab group, 25% of controls at baseline, 40.0% of infliximab group at 1 year Veit 45 59 patients (40 CD, 19 UC) (16.4 +/- 2.2 years) 116 controls (14.6 +/- 4.4 years) Retrospective review Deficiency = 25(OH)D <20ng/mL (<50 nmol/L) = 42.4% of patients with IBD; 26.7% of controls Insufficiency = 25 (OH)D 20–29.9 ng/mL (50–74 nmol/L) = 18.6% of patients with IBD; 10.3% of controls Patients with UC had a non-significantly higher prevalence of vitamin D deficiency compared with the CD participants (50% versus 40%; P = 0.53) Walther 46 90 patients (56 CD, 30 UC, 4 IC) (14.4 +/- 2.2 years) 52 controls (12.9 +/- 3.0 years) 25(OH)D <lower range of normal (not defined) = 29% of steroid-naïve patients, 20% of steroid-treated patients A comprehensive table reviewing these studies can be found in the supplementary material. Legend: IBDU: Inflammatory bowel disease unclassified; IC: indeterminate colitis; TI: terminal ileum. View Large The remaining 13 studies included patients with both CD and UC in their review of vitamin D status. Alkhouri et al (northern USA) found that 62% of patients with IBD had vitamin D deficiency at diagnosis (using a definition of 25(OH)D <12 ng/mL) compared with 75% of controls.25 Laasko et al (Finland) found that 26% of their patients had 25(OH)D <20 ng/mL; 63% of the patients were taking a vitamin D supplement.34 In a separate study, the same group found that 51% of the patients had 25(OH)D <20 ng/mL; 48% were taking a vitamin D supplement.35 Two studies36, 37 found no patients with vitamin D insufficiency or deficiency; however, the laboratory values used to define deficiency were 25(OH)D <10 ng/mL. Due to multiple factors that affect vitamin D status, these studies were further divided into groups based on the factors addressed in each article (see supplementary tables). Latitude is a factor known to affect vitamin D status, with people living greater than 35 degrees from the equator being at higher risk of vitamin D deficiency.38 One study completed in Brazil (23 degrees south of the equator) found no patients with vitamin D insufficiency or deficiency.15 Three studies completed 30–35 degrees from the equator report at least 38% of their patients had vitamin D insufficiency, and at least 15% of patients had vitamin D insufficiency.23, 33, 39 Of the studies completed more than 35 degrees from the equator (n=17), 2 studies reported no patients with vitamin D deficiency. However, these studies defined vitamin D deficiency as 25(OH)D <8 ng/mL36 and insufficiency 25(OH)D <10 ng/mL.37 Skin pigmentation is another factor commonly associated with vitamin D deficiency, with patients with darker skin at higher risk of deficiency.40 Three studies reported that African-American patients with IBD were more likely to have poor vitamin D status than Caucasian patients with IBD.41–43 Three additional studies found that although African Americans with CD were more likely than Caucasians with CD to have poor vitamin D status, their vitamin D status was similar to healthy African-American controls.33, 44, 45 Vitamin D status was also looked at in light of multiple disease characteristics. However, based on the studies reviewed, it is unclear if vitamin D status is affected by disease phenotype, disease location, or disease severity. One study reported that vitamin D deficiency was more common in newly diagnosed patients.41 Three studies reported an association between steroid use and vitamin D status. One of these studies found that patients on steroids are more likely to have poor vitamin D status than patients with nutrition therapy,39 whereas the other 2 studies reported that longer steroid use is associated with lower vitamin D status.44, 46 Vitamin D status was compared between IBD cases and controls in 7 studies.15, 25, 33, 35, 44, 45, 47 Six of these studies reported minimal differences between cases and controls, whereas one study found that controls were more likely to be vitamin D deficient than newly diagnosed patients.25 Other Micronutrients A variety of other micronutrients have also been assessed in pediatric patients with IBD, including vitamin A, vitamin C, vitamin E, vitamin K, other B vitamins, selenium, and zinc (Table 4). Seven studies reviewed serum vitamin A status. All these studies used serum vitamin A or retinol in their analysis. Three studies were completed in the United States, 2 studies in Europe, and 1 study each in Canada and Brazil. Three of the 7 studies found low serum vitamin A in children with IBD. Alkhouri et al found that 16% of patients with IBD had low serum vitamin A.25 Bousvaros et al found that 14% of children with IBD had low serum vitamin A.48 In this study, serum vitamin A deficiency was more common in patients with moderate to severe disease: 36% of patients with moderate or severe CD and 42.8% of patients with moderate to severe UC had low serum levels of vitamin A or vitamin E. Twenty-two percent of the subjects in this study were taking a multivitamin. However, there was no difference in the prevalence of vitamin A deficiency between those taking or not taking a multivitamin preparation. Costa et al found that 40% of patients with active CD had low serum vitamin A, compared with <5% of patients with inactive CD.15 Table 4: Summary Table of Studies Measuring Other Micronutrients Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Vitamin A Greco 49 1 patient with UC (6 years) No controls Case Study Normalserum vitamin A (reference range not defined) Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin A mean = 0.28 mg/L, after treatment = 0.31 mg/L (reference range not defined). Four weeks of exclusive enteral nutrition led to no significant change in vitamin A. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin A (retinol) <20 mg/dL = 16% of IBD patients, 0% of controls Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin A <20 mcg/dl = 14.4% of IBD patients, 0 controls Similar prevalence of vitamin A <20 mcg/dl in CD and UC There was a strong relationship with disease severity and frequency of hypovitaminosis A Costa 15 51 patients with CD from a single outpatient clinic (13.2- 19.4 years) 35 controls Prospective study Low serum vitamin A (value not defined) = 40% of patients with active CD, 5% of patients with inactive CD, 5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Mean retinol, retinol-binding protein, and beta-carotene within normal limits for patients with CD, UC, and controls (reference range not defined) Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Serum retinol within normal limits for all groups (reference range not defined) Vitamin C Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum vitamin C mean = 11.8 mg/L, after treatment = 6.5 mg/L Baseline serum vitamin C within normal limits for 93% of patients (all but one child at the beginning of the study), 73% after treatment Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Compared with control subjects, children with IBD had decreased plasma ascorbic acid concentrations, but all within normal limits. Average serum ascorbic acid concentrations (umol/L, reference range not defined): UC = 295 CD = 273 IBD = 284 Control = 114 Vitamin E Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin E mean = 11.3 mg/L, after treatment = 9.4 mg/L (reference range not defined) Treatment led to statistically significant reductions in mean concentrations of vitamin E. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin E <5 mg/L in 5% of IBD patients, 8% of controls. Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin E <5 mg/L = 6% of patients with IBD Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Low serum vitamin E (reference range not defined) = ~70% of patients with active CD, ~18% of patients with inactive CD, ~5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study No patients with vitamin E deficiency (alpha-tocopherol <9 umol/L or alpha-tocopherol:total lipids >186 umol/g) Children with IBD had increased alpha-tocopherol concentrations compared with controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Alpha-tocopherol normal in all patients (reference range not defined) Selenium Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum selenium before treatment mean = 0.82 umol/L, after treatment = 1.14 umol/L (reference range not defined) At baseline, 93% had serum selenium within normal limits. Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Serum selenium <1.28 umol/L Mean serum selenium within normal limits for patients with IBD and controls. Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum selenium normal in all patients (reference range not defined) Zinc Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Serum zinc <70 mg/dL = 40% of IBD patients, 19% of controls Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Serum zinc deficiency (level not defined): ~6% with inactive disease, ~4% with active disease, ~5% of controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum zinc normal in all patients (reference range not defined). Mean serum zinc levels lower for patients with CD than controls (8.47 umol/L CD vs 11.49 control) Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Serum zinc <70 μg/dL = 51% of patients with CD Average zinc level lower in patients with patients with PCDAI >30 (67.9 μg/dL) than patients with PCDAI <30 (80.2 μg/dL) Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Zinc <70 μg/dL = 17% of patients with CD Griffin 52 15 patients with CD on 12 mg/day zinc (15.4 +/- 1.7 years) 15 controls (14.8 +/- 1.5 years) Prospective study Plasma zinc <0.8 mg/L = 20% of patients with CD, 0% of controls Other Greco 49 1 patient with UC (6 years) Case study vitamins B1, B6 normal (reference range not defined) Nowak 53 111 (63 CD, 48 UC) (6–18 years) No controls Cross sectional study PIVKA-II concentrations >2 ng/mL as measurement of vitamin K deficiency = 54% of patients with CD and 43.7% of patients with UC Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Vitamin A Greco 49 1 patient with UC (6 years) No controls Case Study Normalserum vitamin A (reference range not defined) Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin A mean = 0.28 mg/L, after treatment = 0.31 mg/L (reference range not defined). Four weeks of exclusive enteral nutrition led to no significant change in vitamin A. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin A (retinol) <20 mg/dL = 16% of IBD patients, 0% of controls Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin A <20 mcg/dl = 14.4% of IBD patients, 0 controls Similar prevalence of vitamin A <20 mcg/dl in CD and UC There was a strong relationship with disease severity and frequency of hypovitaminosis A Costa 15 51 patients with CD from a single outpatient clinic (13.2- 19.4 years) 35 controls Prospective study Low serum vitamin A (value not defined) = 40% of patients with active CD, 5% of patients with inactive CD, 5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Mean retinol, retinol-binding protein, and beta-carotene within normal limits for patients with CD, UC, and controls (reference range not defined) Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Serum retinol within normal limits for all groups (reference range not defined) Vitamin C Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum vitamin C mean = 11.8 mg/L, after treatment = 6.5 mg/L Baseline serum vitamin C within normal limits for 93% of patients (all but one child at the beginning of the study), 73% after treatment Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Compared with control subjects, children with IBD had decreased plasma ascorbic acid concentrations, but all within normal limits. Average serum ascorbic acid concentrations (umol/L, reference range not defined): UC = 295 CD = 273 IBD = 284 Control = 114 Vitamin E Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin E mean = 11.3 mg/L, after treatment = 9.4 mg/L (reference range not defined) Treatment led to statistically significant reductions in mean concentrations of vitamin E. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin E <5 mg/L in 5% of IBD patients, 8% of controls. Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin E <5 mg/L = 6% of patients with IBD Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Low serum vitamin E (reference range not defined) = ~70% of patients with active CD, ~18% of patients with inactive CD, ~5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study No patients with vitamin E deficiency (alpha-tocopherol <9 umol/L or alpha-tocopherol:total lipids >186 umol/g) Children with IBD had increased alpha-tocopherol concentrations compared with controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Alpha-tocopherol normal in all patients (reference range not defined) Selenium Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum selenium before treatment mean = 0.82 umol/L, after treatment = 1.14 umol/L (reference range not defined) At baseline, 93% had serum selenium within normal limits. Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Serum selenium <1.28 umol/L Mean serum selenium within normal limits for patients with IBD and controls. Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum selenium normal in all patients (reference range not defined) Zinc Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Serum zinc <70 mg/dL = 40% of IBD patients, 19% of controls Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Serum zinc deficiency (level not defined): ~6% with inactive disease, ~4% with active disease, ~5% of controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum zinc normal in all patients (reference range not defined). Mean serum zinc levels lower for patients with CD than controls (8.47 umol/L CD vs 11.49 control) Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Serum zinc <70 μg/dL = 51% of patients with CD Average zinc level lower in patients with patients with PCDAI >30 (67.9 μg/dL) than patients with PCDAI <30 (80.2 μg/dL) Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Zinc <70 μg/dL = 17% of patients with CD Griffin 52 15 patients with CD on 12 mg/day zinc (15.4 +/- 1.7 years) 15 controls (14.8 +/- 1.5 years) Prospective study Plasma zinc <0.8 mg/L = 20% of patients with CD, 0% of controls Other Greco 49 1 patient with UC (6 years) Case study vitamins B1, B6 normal (reference range not defined) Nowak 53 111 (63 CD, 48 UC) (6–18 years) No controls Cross sectional study PIVKA-II concentrations >2 ng/mL as measurement of vitamin K deficiency = 54% of patients with CD and 43.7% of patients with UC A comprehensive table reviewing these studies can be found in the supplementary material online. Legend: BMI: body mass index; IC: Indeterminate colitis; ID: Iron deficiency; IDA: iron deficiency anemia; TI: Terminal Ileum. View Large Table 4: Summary Table of Studies Measuring Other Micronutrients Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Vitamin A Greco 49 1 patient with UC (6 years) No controls Case Study Normalserum vitamin A (reference range not defined) Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin A mean = 0.28 mg/L, after treatment = 0.31 mg/L (reference range not defined). Four weeks of exclusive enteral nutrition led to no significant change in vitamin A. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin A (retinol) <20 mg/dL = 16% of IBD patients, 0% of controls Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin A <20 mcg/dl = 14.4% of IBD patients, 0 controls Similar prevalence of vitamin A <20 mcg/dl in CD and UC There was a strong relationship with disease severity and frequency of hypovitaminosis A Costa 15 51 patients with CD from a single outpatient clinic (13.2- 19.4 years) 35 controls Prospective study Low serum vitamin A (value not defined) = 40% of patients with active CD, 5% of patients with inactive CD, 5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Mean retinol, retinol-binding protein, and beta-carotene within normal limits for patients with CD, UC, and controls (reference range not defined) Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Serum retinol within normal limits for all groups (reference range not defined) Vitamin C Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum vitamin C mean = 11.8 mg/L, after treatment = 6.5 mg/L Baseline serum vitamin C within normal limits for 93% of patients (all but one child at the beginning of the study), 73% after treatment Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Compared with control subjects, children with IBD had decreased plasma ascorbic acid concentrations, but all within normal limits. Average serum ascorbic acid concentrations (umol/L, reference range not defined): UC = 295 CD = 273 IBD = 284 Control = 114 Vitamin E Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin E mean = 11.3 mg/L, after treatment = 9.4 mg/L (reference range not defined) Treatment led to statistically significant reductions in mean concentrations of vitamin E. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin E <5 mg/L in 5% of IBD patients, 8% of controls. Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin E <5 mg/L = 6% of patients with IBD Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Low serum vitamin E (reference range not defined) = ~70% of patients with active CD, ~18% of patients with inactive CD, ~5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study No patients with vitamin E deficiency (alpha-tocopherol <9 umol/L or alpha-tocopherol:total lipids >186 umol/g) Children with IBD had increased alpha-tocopherol concentrations compared with controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Alpha-tocopherol normal in all patients (reference range not defined) Selenium Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum selenium before treatment mean = 0.82 umol/L, after treatment = 1.14 umol/L (reference range not defined) At baseline, 93% had serum selenium within normal limits. Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Serum selenium <1.28 umol/L Mean serum selenium within normal limits for patients with IBD and controls. Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum selenium normal in all patients (reference range not defined) Zinc Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Serum zinc <70 mg/dL = 40% of IBD patients, 19% of controls Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Serum zinc deficiency (level not defined): ~6% with inactive disease, ~4% with active disease, ~5% of controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum zinc normal in all patients (reference range not defined). Mean serum zinc levels lower for patients with CD than controls (8.47 umol/L CD vs 11.49 control) Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Serum zinc <70 μg/dL = 51% of patients with CD Average zinc level lower in patients with patients with PCDAI >30 (67.9 μg/dL) than patients with PCDAI <30 (80.2 μg/dL) Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Zinc <70 μg/dL = 17% of patients with CD Griffin 52 15 patients with CD on 12 mg/day zinc (15.4 +/- 1.7 years) 15 controls (14.8 +/- 1.5 years) Prospective study Plasma zinc <0.8 mg/L = 20% of patients with CD, 0% of controls Other Greco 49 1 patient with UC (6 years) Case study vitamins B1, B6 normal (reference range not defined) Nowak 53 111 (63 CD, 48 UC) (6–18 years) No controls Cross sectional study PIVKA-II concentrations >2 ng/mL as measurement of vitamin K deficiency = 54% of patients with CD and 43.7% of patients with UC Study Patient and Study Characteristics Pertinent Results / Conclusions / Findings Vitamin A Greco 49 1 patient with UC (6 years) No controls Case Study Normalserum vitamin A (reference range not defined) Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin A mean = 0.28 mg/L, after treatment = 0.31 mg/L (reference range not defined). Four weeks of exclusive enteral nutrition led to no significant change in vitamin A. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin A (retinol) <20 mg/dL = 16% of IBD patients, 0% of controls Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin A <20 mcg/dl = 14.4% of IBD patients, 0 controls Similar prevalence of vitamin A <20 mcg/dl in CD and UC There was a strong relationship with disease severity and frequency of hypovitaminosis A Costa 15 51 patients with CD from a single outpatient clinic (13.2- 19.4 years) 35 controls Prospective study Low serum vitamin A (value not defined) = 40% of patients with active CD, 5% of patients with inactive CD, 5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Mean retinol, retinol-binding protein, and beta-carotene within normal limits for patients with CD, UC, and controls (reference range not defined) Sikora 18 154 patients newly diagnosed with IBD (80 CD, 74 UC) (11.3+/-3.7 years) 64 controls (10.7+/- 4.6 years) Retrospective study Serum retinol within normal limits for all groups (reference range not defined) Vitamin C Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum vitamin C mean = 11.8 mg/L, after treatment = 6.5 mg/L Baseline serum vitamin C within normal limits for 93% of patients (all but one child at the beginning of the study), 73% after treatment Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Compared with control subjects, children with IBD had decreased plasma ascorbic acid concentrations, but all within normal limits. Average serum ascorbic acid concentrations (umol/L, reference range not defined): UC = 295 CD = 273 IBD = 284 Control = 114 Vitamin E Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline plasma vitamin E mean = 11.3 mg/L, after treatment = 9.4 mg/L (reference range not defined) Treatment led to statistically significant reductions in mean concentrations of vitamin E. Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Vitamin E <5 mg/L in 5% of IBD patients, 8% of controls. Bousvaros 48 97 patients (61 CD, 36 UC) (2.6 – 26.2 years) 23 controls with GI illness but no IBD Prospective study Vitamin E <5 mg/L = 6% of patients with IBD Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Low serum vitamin E (reference range not defined) = ~70% of patients with active CD, ~18% of patients with inactive CD, ~5% of controls Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study No patients with vitamin E deficiency (alpha-tocopherol <9 umol/L or alpha-tocopherol:total lipids >186 umol/g) Children with IBD had increased alpha-tocopherol concentrations compared with controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Alpha-tocopherol normal in all patients (reference range not defined) Selenium Akobeng 50 15 patients with active CD starting enteral nutrition therapy (6.8–15.7 years) No controls Prospective Study Baseline serum selenium before treatment mean = 0.82 umol/L, after treatment = 1.14 umol/L (reference range not defined) At baseline, 93% had serum selenium within normal limits. Hoffenberg 51 24 (12 CD, 12 UC) (CD 14.7 +/-2.3 years; UC 11.3 +/-3.5 years) 23 controls (13.0+/-3.2 years) Prospective study Serum selenium <1.28 umol/L Mean serum selenium within normal limits for patients with IBD and controls. Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum selenium normal in all patients (reference range not defined) Zinc Alkhouri 25 61 patients (46 CD, 12 UC, 3 IC) (12.3 ± 3.9 years) 61 age-matched controls Retrospective study Serum zinc <70 mg/dL = 40% of IBD patients, 19% of controls Costa 15 51 patients with CD from single outpatient clinic (13.2- 19.4 years) 35 age-matched controls Prospective study Serum zinc deficiency (level not defined): ~6% with inactive disease, ~4% with active disease, ~5% of controls Sikora 18 154 patients (80:CD, 74: UC) (11.3 ± 3.7 years) 64 age-matched controls (10.7 ± 4.6 years) Retrospective study Serum zinc normal in all patients (reference range not defined). Mean serum zinc levels lower for patients with CD than controls (8.47 umol/L CD vs 11.49 control) Song 13 71 newly diagnosed patients with CD from a single center (12–15 years) Prospective study Serum zinc <70 μg/dL = 51% of patients with CD Average zinc level lower in patients with patients with PCDAI >30 (67.9 μg/dL) than patients with PCDAI <30 (80.2 μg/dL) Hartman 23 68 consecutive children from single outpatient clinic (57 CD; 11 UC) (13.9 ± 3.2 years) No controls Prospective study Zinc <70 μg/dL = 17% of patients with CD Griffin 52 15 patients with CD on 12 mg/day zinc (15.4 +/- 1.7 years) 15 controls (14.8 +/- 1.5 years) Prospective study Plasma zinc <0.8 mg/L = 20% of patients with CD, 0% of controls Other Greco 49 1 patient with UC (6 years) Case study vitamins B1, B6 normal (reference range not defined) Nowak 53 111 (63 CD, 48 UC) (6–18 years) No controls Cross sectional study PIVKA-II concentrations >2 ng/mL as measurement of vitamin K deficiency = 54% of patients with CD and 43.7% of patients with UC A comprehensive table reviewing these studies can be found in the supplementary material online. Legend: BMI: body mass index; IC: Indeterminate colitis; ID: Iron deficiency; IDA: iron deficiency anemia; TI: Terminal Ileum. View Large Four studies did not find low levels of serum vitamin A. Three of these studies had relatively small sample sizes.49–51 Akobeng et al included 15 patients with active CD and found no patients with low serum vitamin A before or after exclusive enteral nutrition.50 An additional study that included 154 children with IBD and excluded patients with multivitamin supplementation found no patients with low serum levels of vitamin A.18 Disease severity was not described in this study. Six studies reviewed serum vitamin E status in patients with IBD. Three of these studies found that all patients had serum vitamin E levels within normal limits.18, 50, 51 These studies included patients with CD and UC. One study found that 5% of patients with IBD and 8% of controls had low serum vitamin E.25 One study reported that 6% of patients with IBD had low serum vitamin E,48 and another study reported that 70% of patients with active disease, 18% of patients with inactive disease, and 5% of controls had low serum vitamin E.15 Six studies reported on serum zinc levels in patients with IBD. Five of these studies found patients with low serum zinc levels. One study found that 40% of patients with IBD had zinc deficiency, compared with 19% of controls.25 One study reported that 51% of newly diagnosed patients with IBD had low serum zinc levels.13 One study reported that 17% of outpatients with IBD had low serum zinc.23 Another study found that 20% of patients had low plasma zinc after following a 12-mg zinc diet for 2 weeks.52 Two studies with relatively small sample sizes looked at serum levels of vitamin C.50, 51 Only 1 patient out of a combined total of 29 was found to have low serum vitamin C. Three studies reviewed serum selenium status in patients with IBD.18, 50, 51 Only 1 patient out of a combined total of 183 was found to have a low serum selenium level. We found 1 case report that looked at other B vitamins in a patient with UC49 and 1 cross-sectional study which looked at vitamin K using PIVKA-II concentrations.53 This study found vitamin K deficiency in 54% of their patients with CD and in 43.7% of their patients with UC. DISCUSSION The studies included in this review screened for various micronutrient deficiencies using a variety of different laboratory indices over of the course of the disease. This confirms our assertion that the literature lacks evidence-based recommendations for micronutrient assessment in pediatric patients with IBD. Iron Iron deficiency is common in IBD, and as many as 95% of patients have been reported to be iron deficient at diagnosis; additionally, up to 70% of patients may have iron deficiency 2 years after diagnosis. This may be due to poor disease control, although studies showed that iron deficiency may be present in patients with CD and UC with active or inactive disease. Other factors which could contribute to continued iron deficiency in patients with IBD include insufficient oral intake and/or inadequate supplementation in particular, given that studies have shown iron deficiency may continue despite oral supplementation.17 These results suggest that iron studies should be monitored during supplementation to ensure efficacy of supplement dose and method. Although patients with inactive disease have lower serum ferritin levels than patients with active disease,15 the role of ferritin as an acute phase reactant complicates its use in diagnosis of iron deficiency. Patients with significant inflammation and blood loss may have discordant iron studies with elevated ferritin and low iron, whereas a patient with minimal inflammation but ongoing iron deficiency would have both a low ferritin and low iron. Given the above data, we recommend screening for iron deficiency in children with IBD using CRP, ferritin, iron, and TIBC, as the percentage of transferrin saturation can be calculated using serum iron and TIBC. Iron deficiency should be defined as, • CRP <10 mg/L and ferritin <30 ug/L • CRP >10 mg/L and ferritin <100 ug/L • Transferrin saturation <16% when CRP not available20, 54 Soluble transferrin receptor may also be a useful single test to identify iron deficiency anemia in place of a whole iron panel, but more studies need to be done to validate its use. As recommended in the recent position paper by the Porto IBD Group of ESPGHAN,11 we also suggest that patients with CD and UC be screened for iron status at diagnosis and regularly throughout the course of the disease, regardless of disease activity, disease location, and supplement use. Vitamin B12 With the exception of 2 studies, vitamin B12 deficiency was rare (<2%) in the populations studied. Of the studies that did report vitamin B12 deficiency, one found that that ileal or ileocolonic resection increased the risk of abnormal serum vitamin B12 concentrations.26 Until more data are available, we do not recommend routinely screening for vitamin B12 deficiency in all pediatric patients with IBD, but in agreement with the ESPGHAN workgroup recommendations,11 we concur with vitamin B12 screening in patients with a history of ileal or ileocolonic resection and in those patients with suspected vitamin B12 malabsorption. Screening for B12 deficiency should also be considered in patients with UC with an ileal pouch anal anastomosis. Future studies should consider the use of serum methylmalonic acid levels in addition to serum vitamin B12 concentrations. Folate As reported in only 2 reviewed studies, folate deficiency was rare in children with IBD (0%–2% of patients). Both of the studies reporting a high prevalence of folate deficiency were completed in countries where folic acid fortification of food was not mandated at the time of the studies.55 We hypothesize that the lack of mandated folic acid fortification of food resulted in the increased incidence of folate deficiency in these 2 studies. Thus, in countries where foods are fortified with folic acid, we do not recommend routine testing of RBC folate. However, in countries without routine folic acid supplementation in foods, assessment for folate deficiency may be warranted. This is at odds with the recommendations from the ESPGHAN group, likely because we focused our review only on pediatric patients with IBD, in whom folate deficiency has been reported less frequently than in adults with IBD.11 We agree that patients treated with methotrexate should receive additional prophylactic folic acid supplementation because methotrexate inhibits the uptake of folate. Vitamin D Vitamin D insufficiency and deficiency were common in our studies reviewed. All but 3 studies found patients with vitamin D deficiency or insufficiency. One Brazilian study did not report vitamin D deficiency.15 The low incidence of vitamin D deficiency in this study may be due to two factors: the proximity of Brazil to the equator and the lack of disclosure of the cutoff values used by the investigators to diagnose vitamin D deficiency. The other 2 studies that did not report vitamin D deficiency were defined by laboratory cutoff values <10 ng/mL. In the 18 studies that found vitamin D deficiency and insufficiency, as many as 98% of patients with IBD were found to be vitamin D deficient or insufficient. This is consistent with a recent meta-analysis of adult patients with CD by Sandghian, who reported that about 50% of patients with CD have poor vitamin D status.56 Distance from the equator is known to be a factor in vitamin D status, with patients living more than 35 degrees from the equator at a higher risk of poor vitamin D status. Three studies in our review from areas 30–35 degrees from the equator found >15% of patients had vitamin D deficiency, and >38% of patients had vitamin D insufficiency, suggesting that even patients living less than 35 degrees from the equator may have poor vitamin D status.23, 33, 39 Sandghian et al reported similar findings in adults with a significant correlation between latitude and vitamin D levels, with patients living further from the equator having lower levels. Based on our reviewed studies, it is unclear if disease phenotype, disease location, or disease severity change the incidence of vitamin D deficiency. Sandghian et al reported that adults with lower vitamin D status had higher disease activity, but this association is not as clear in children. Recent studies suggest that inflammatory bowel disease causes vitamin D deficiency, and in our review, elevated ESR and steroid use did increase the risk of poor vitamin D status.39, 42, 43, 46 African-American patients with IBD are more likely to be vitamin D deficient than Caucasian patients with IBD. However, they may not be more likely to have vitamin D deficiency than African-American controls. Based on the studies reviewed, it is unclear whether patients with IBD are more likely than healthy children to have vitamin D deficiency. Three studies33, 35, 44 reported minimal differences between cases and controls, and 1 study reported that controls were more likely to be deficient.25 Sandghian et al found conflicting information in their meta-analysis on vitamin D status in adults with CD.56 They found that adults with CD had lower vitamin D levels than controls. In the studies included in this review, vitamin D deficiency was found in a variety of IBD patient subgroups including newly diagnosed patients, patients in remission, patients with active disease, patients taking vitamin D supplements, patients with varying skin pigmentation, and patients with different disease phenotypes. We therefore recommend checking 25(OH)D at diagnosis and at least annually for all patients with IBD. These measurements may be deferred in patients living closer to the equator based on clinical judgment. In northern latitudes, we support checking vitamin D in the fall or spring when the values are assumed to be at the annual mean. Although not validated in children, seasonal vitamin D calculators may be useful to calculate annual mean vitamin D levels when fall or spring measurements are not feasible47, 57–60 Other Micronutrients Three studies found low serum vitamin A values in children with IBD. Two of these studies found that patients with active disease were more likely to have low serum values of vitamin A. This trend is likely related to inflammation instead of true vitamin A deficiency, as serum vitamin A levels decrease during times of metabolic stress.61 None of the reviewed studies described symptoms or signs of vitamin A deficiency. Four studies did not find low levels of serum vitamin A. Based on conflicting information from the 7 studies reviewed and the possibility of falsely identifying deficiency in the setting of inflammation, we do not recommend routinely checking vitamin A levels in patients with IBD. Six studies reported on serum vitamin E status. Three studies found that all patients had vitamin E levels within normal limits. One study found that controls were more likely to have low serum vitamin E than patients with IBD. Two studies reported that patients with IBD had low serum vitamin E. Because vitamin E levels also decrease with metabolic stress, it is unclear if these patients actually had vitamin E deficiency61 or had lowered levels due to their disease activity. Based on this data, more research is needed to determine if vitamin E deficiency occurs in children with IBD. Until more information is available, we do not recommend routinely checking vitamin E levels for patients with IBD. Five of the 6 studies reviewed found patients with low serum zinc levels. Zinc deficiency was most common in newly diagnosed patients with CD. However, it was also reported in 17% of screened outpatients. This suggests that zinc deficiency can occur regardless of disease status and duration. Up to 20% of patients had low serum zinc levels after a high oral zinc intake, suggesting that aggressive oral supplementation may be warranted. Because serum zinc levels decrease during metabolic stress, the rate of actual zinc deficiency may be less than what is described in these studies.61 However, diarrhea (a common symptom in IBD) increases zinc excretion and can decrease total body zinc. The Porto IBD Group of ESPGHAN recommended against routine measurement of zinc despite recognition that zinc deficiency is common in children with CD and zinc consumption may be inadequate in children with IBD.11 The studies in this review, although limited in sample size, frequently uncovered zinc deficiency—and at a higher rate than healthy controls. We therefore suggest screening for zinc deficiency in all patients with CD at diagnosis and annually. Rechecking labs while on supplementation is also warranted. Based on the studies presented, we do not recommend routinely checking serum vitamin C concentrations or screening for selenium deficiency in children with IBD. From the data presented in this review, we created a recommended nutrition laboratory monitoring schedule for children with IBD (Table 5). Because multiple nutrition labs are affected by inflammation and metabolic stress, we recommend checking nutrition labs when patients have inactive disease. If laboratory measurements are collected during times of high disease activity, inflammation should be taken into account when interpreting lab results. Table 5: Recommended Nutrition Lab Monitoring Schedule Iron Studies (ferritin, serum iron, and TIBC) and CRP At diagnosis and at least annually Reassess during supplementation to determine response Vitamin D 25(OH)D At diagnosis and at least annually In northern latitudes, check in fall or spring or consider using a vitamin D calculator to determine annual mean Zinc At diagnosis and at least annually for patients with CD Reassess during supplementation to determine response Vitamin B12 Do not routinely measure Consider in patients with a history of ileal or ileocolonic resection or ileal pouch anal anastamosis Consider in patients where vitamin B12 malabsorption is suspected Consider obtaining serum methylmalonic acid when measuring serum vitamin B12 RBC folate Do not routinely measure in countries with folic acid fortification Consider checking annually in countries without folic acid fortification Iron Studies (ferritin, serum iron, and TIBC) and CRP At diagnosis and at least annually Reassess during supplementation to determine response Vitamin D 25(OH)D At diagnosis and at least annually In northern latitudes, check in fall or spring or consider using a vitamin D calculator to determine annual mean Zinc At diagnosis and at least annually for patients with CD Reassess during supplementation to determine response Vitamin B12 Do not routinely measure Consider in patients with a history of ileal or ileocolonic resection or ileal pouch anal anastamosis Consider in patients where vitamin B12 malabsorption is suspected Consider obtaining serum methylmalonic acid when measuring serum vitamin B12 RBC folate Do not routinely measure in countries with folic acid fortification Consider checking annually in countries without folic acid fortification View Large Table 5: Recommended Nutrition Lab Monitoring Schedule Iron Studies (ferritin, serum iron, and TIBC) and CRP At diagnosis and at least annually Reassess during supplementation to determine response Vitamin D 25(OH)D At diagnosis and at least annually In northern latitudes, check in fall or spring or consider using a vitamin D calculator to determine annual mean Zinc At diagnosis and at least annually for patients with CD Reassess during supplementation to determine response Vitamin B12 Do not routinely measure Consider in patients with a history of ileal or ileocolonic resection or ileal pouch anal anastamosis Consider in patients where vitamin B12 malabsorption is suspected Consider obtaining serum methylmalonic acid when measuring serum vitamin B12 RBC folate Do not routinely measure in countries with folic acid fortification Consider checking annually in countries without folic acid fortification Iron Studies (ferritin, serum iron, and TIBC) and CRP At diagnosis and at least annually Reassess during supplementation to determine response Vitamin D 25(OH)D At diagnosis and at least annually In northern latitudes, check in fall or spring or consider using a vitamin D calculator to determine annual mean Zinc At diagnosis and at least annually for patients with CD Reassess during supplementation to determine response Vitamin B12 Do not routinely measure Consider in patients with a history of ileal or ileocolonic resection or ileal pouch anal anastamosis Consider in patients where vitamin B12 malabsorption is suspected Consider obtaining serum methylmalonic acid when measuring serum vitamin B12 RBC folate Do not routinely measure in countries with folic acid fortification Consider checking annually in countries without folic acid fortification View Large We believe that children with IBD are at a higher risk than the general population for multiple micronutrient deficiencies, regardless of their disease activity or phenotype. 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APPENDIX A: OVID SEARCH STRATEGY 1 exp inflammatory bowel diseases/ or exp colitis, ulcerative/ or exp crohn disease 2 (crohn* or ulcerative colitis or inflammatory bowel*).mp. 3 1 or 2 4 limit 3 to english language 5 limit 4 to yr="1996 -Current" 6 exp micronutrients/ or micronutrient*.mp. 7 exp nutritional status/ or nutritional status*.mp. 8 exp nutrition assessment/ or nutrition* assessment*.mp. 9 exp avitaminosis/ or avitaminosis*.mp. 10 exp deficiency diseases/ or deficiency disease*.mp. 11 nutrition* deficien*.mp. 12 exp folic acid/ or folic acid*.mp. or folate*.mp. 13 vitamin b12.mp. or exp Vitamin B 12/ or vitamin b 12.mp. 14 exp vitamin b 12 deficiency/ or vitamin b 12 deficien*.mp. or vitamin b12 deficien*.mp. 15 cobalamin*.mp. 16 exp copper/ or copper*.mp. 17 exp selenium/ or selenium*.mp. 18 exp iron/ or exp anemia, iron-deficiency/ or irons.mp. or iron deficien*.mp. 19 exp zinc/ or zinc*.mp. 20 exp 24,25-Dihydroxyvitamin D 3/ 21 (24,25-dihydroxyvitamin d 3* or 24,25-dihydroxyvitamin d3*).mp. 22 (25-hydroxyvitamin d2 or 25-hydroxyvitamin d 2).mp. or 25-Hydroxyvitamin D 2/ 23 exp cholecalciferol/ or cholecalciferol*.mp. 24 exp ergocalciferols/ or ergocalciferol*.mp. 25 exp Vitamin A/ or vitamin a.mp. 26 exp Vitamin D/ or vitamin d.mp. 27 exp Vitamin E/ or vitamin e.mp. 28 exp vitamin d deficiency/ or vitamin d deficien*.mp. 29 exp vitamin e deficiency/ or vitamin e deficien*.mp. 30 exp vitamin k deficiency/ or vitamin k deficien*.mp. 31 exp vitamin a deficiency/ or vitamin a deficien*.mp. 32 exp vitamin k/ or vitamin k.mp. 33 or/6-32 34 5 and 33 35 limit 34 to "all child (0 to 18 years)" 36 (child* or pediatr* or paediatr* or infant* or baby or babies or adolescen* or girl or girls or boy or boys or newborn* or teen or teenage* or kid or kids or toddler*).mp. 37 34 and 36 38 35 or 37 © 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - A Systematic Review of Micronutrient Deficiencies in Pediatric Inflammatory Bowel Disease
JO - Inflammatory Bowel Diseases
DO - 10.1093/ibd/izy271
DA - 2019-02-21
UR - https://www.deepdyve.com/lp/oxford-university-press/a-systematic-review-of-micronutrient-deficiencies-in-pediatric-0nK4LYLu99
SP - 445
VL - 25
IS - 3
DP - DeepDyve
ER -