Abstract
OBJECTIVE. The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease.
METHODS. Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment.
RESULTS. A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests.
CONCLUSION. The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.
Laboratory evaluation to screen for evidence of inflammatory bowel disease (IBD) is performed routinely for children with chronic abdominal pain or diarrhea and can help both to establish a diagnosis and to serve as a baseline for management. When these children are ill with concomitant bleeding, weight loss, and abdominal tenderness, generally prompt referral to a pediatric gastroenterologist is made. For children with milder symptoms, such as only occasional abdominal discomfort or intermittent episodes of loose stools, the presence of normal laboratory parameters might reassure the primary health care provider that IBD is not present. By using a large, prospective, pediatric IBD database, we sought to identify the frequency with which children with newly diagnosed IBD present with normal laboratory values in the tests commonly used to screen for IBD.
METHODS
Patients
All data included in this report were obtained from the database of the Pediatric IBD Collaborative Research Group Registry. This registry was initiated in January 2002 by 18 US and Canadian pediatric gastroenterology centers with significant clinical expertise in IBD, as a method of describing the contemporary natural history of IBD in patients with newly diagnosed disease who had not reached their 16th birthday. Diagnoses of Crohn disease (CD) and ulcerative colitis (UC) were made at each of the 18 participating centers on the basis of conventional clinical, laboratory, radiologic, endoscopic, and histologic criteria. Patients with indeterminate colitis were not included in this review. For each enrolled subject, clinical and demographic characteristics, including type and extent of IBD and disease activity assessment, were recorded at the time of initial diagnosis. Laboratory data, including hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate (ESR), were also recorded on standardized forms and transmitted to a central data repository. Approval for the registry was received from the human subjects review committee at each participating institution. Informed consent was obtained from all families.
Laboratory Values
Hemoglobin levels were considered normal if they were ≥11.0 g/L for patients of either gender who were <6 years of age, ≥11.5 g/L for patients of either gender who were ≥6 years and <12 years of age, ≥12 g/L for female patients who were ≥12 years of age, and ≥13 g/L for male patients who were ≥12 years of age.1 Platelet counts of ≤450 × 109 platelets per L, albumin levels of ≥3.4 g/L, and ESR values of <20 mm/hour were considered normal for all ages and both genders. All laboratory testing was performed locally and not at a centralized laboratory.
Disease Activity
At the time of diagnosis, the attending physician categorized disease activity with physician global assessment (PGA). This assessment was made after the history and physical examination was completed but before the laboratory data were known; patients were classified as having quiescent, mild, moderate, or severe disease. The PGA has been used as the standard with which other, more-quantitative instruments to assess the activity of CD (eg, pediatric CD activity index) that include laboratory data have been compared. Previous studies showed excellent correlation between the PGA and other indices of disease activity.2,3 There has been no validated instrument for assessing the activity of UC in either adults or children, and usually the PGA is used.
Statistical Analyses
Data are shown as mean ± SD. Differences between the normal and abnormal laboratory results for each of the 4 tests studied were evaluated by using the χ2 test and Fisher's exact test. In addition, the χ2 test was used for analysis of disease location in relation to disease severity. Differences between CD and UC for the disease severity groupings were evaluated by using t tests. The Mann-Whitney U test and 1-way analysis of variance with multiple comparisons were used for comparison of disease location with the number of abnormal laboratory tests. The McNemar test was used for correlations between normal and abnormal laboratory values. P < .05 was considered significant for all tests; in the case of multiple pairwise tests, a significance level of 0.05/k was used, where k represents the number of tests being performed, to maintain the overall error rate of .05. SPSS 12.0.1 for Windows (SPSS, Chicago, IL) was used by the Pediatric IBD Collaborative Research Group Registry statisticians (Ms Langton and Ms Lerer) to conduct the statistical analyses.
RESULTS
The characteristics of the study population are shown in Table 1. A total of 526 participants (58% male) were diagnosed as having CD (n = 392) or UC (n = 134). The age at onset of disease was 11.6 ± 3.1 years (mean ± SD). Seventy-one percent of children had moderate/severe disease at the time of diagnosis.
Characteristics of the Study Population
The frequency of normal laboratory tests for children with newly diagnosed CD or UC is shown in Table 2. Among children who presented with mild disease activity and had complete laboratory data for evaluation, normal values for all 4 laboratory tests were found for 21% of CD participants (22 of 105 patients) and 54% of UC participants (21 of 39 patients). Patients with moderate/severe IBD were more likely to have ≥1 abnormal laboratory test, but 4% (14 of 353 patients) had normal values for all 4 laboratory tests.
Frequency of Normal Laboratory Values at Diagnosis
When tests were examined individually, ESR was the least likely of the laboratory tests to yield normal results, with normal ESR results being found for 26% of all subjects (129 of 497 patients) (Table 3). Even for subjects with moderate/severe disease, a normal platelet count or albumin level was found for 43% and 50% of patients, respectively, whereas 24% had normal hemoglobin levels and 18% had normal ESR results. Children with mild CD had normal laboratory results more frequently than did children with either moderate or severe CD (Table 3). Similarly, patients with mild UC had normal ESR values, platelet counts, and hemoglobin levels more frequently than did those with either moderate or severe disease (Table 3). Whereas rates of normal albumin levels were similar for UC participants with mild and moderate disease, both groups were more likely to have normal albumin levels than were children with severe UC (Table 3).
Frequency of Normal Individual Laboratory Values
The numerical values of ESRs, platelet counts, and albumin levels, are shown in Fig 1. These numerical values for mild, moderate, and severe CD and UC reflect the frequency of normal laboratory findings discussed in the previous section, with greater disease severity having median values further from the normal outer range. Mean values of ESR (P = .026) and platelet counts (P < .001) in mild CD were higher than those in mild UC. Mean values of ESR (P = .026), platelet counts (P = .021), and albumin levels (P = .001) were worse in moderate CD than in moderate UC.
Individual laboratory values in new-onset IBD. Box plots are shown for the distribution of the numerical values of ESR (A), albumin level (B), and platelet count (C) for participants with CD and UC at the time of diagnosis. Box plots show median values within each box (25th and 75th percentiles at the bottom and top of each box, respectively); error bars extending from each box are the 5th and 95th percentiles, and circles indicate values outside these representations.
Because normal hemoglobin levels vary with age and gender, comparisons were made for patients 6 to 12 years of age and ≥12 years of age, to minimize the age effect. For patients 6 to 12 years of age, the hemoglobin level in mild CD (12.1 ± 4.0 g/L, mean ± SD; n = 47) was similar to the hemoglobin level in mild UC (12.2 ± 1.3 g/L; n = 19), and the hemoglobin level in moderate CD (11.2 ± 2.4 g/L; n = 69) was similar to that in moderate UC (10.4 ± 1.8 g/L; n = 28). However, the hemoglobin level in severe CD (10.7 ± 1.5 g/L; n = 30) was higher than that in severe UC (8.3 ± 0.7 g/L; n = 4; P = .006). Similarly, for patients ≥12 years of age, the hemoglobin levels in mild CD (12.6 ± 3.4 g/L; n = 49) and mild UC (12.5 ± 1.5 g/L; n = 15) and in moderate CD (11.3 ± 1.5 g/L; n = 121) and moderate UC (11.6 ± 1.6 g/L; n = 35) were similar to each other. Unlike in the younger age group, however, hemoglobin levels in severe CD (10.5 ± 1.8 g/L; n = 33) and severe UC (9.4 ± 1.8 g/L; n = 15) were similar.
As shown in Table 1, CD was more likely to involve multiple regions of the gastrointestinal tract than a single location (ie, upper gastrointestinal tract, small bowel, or colon). For UC, involvement of the entire colon was the most likely distribution of disease at the time of diagnosis. Figure 2A reveals no association between location of disease and severity of disease in CD. There was no clear pattern for the number of normal laboratory values for participants with CD (Fig 3A). Pairwise analysis between the different locations of bowel affected by CD revealed colon-only disease was more likely to have normal tests than small bowel and ascending colon disease (P = .034) or disease involving the upper gastrointestinal tract and small bowel with or without any region of the colon (P < .001). However, these findings do not take into account the length of mucosa involved in each of these regions. As might be expected, there was a direct correlation between disease severity and extent of bowel involved in UC (Fig 2B) and the number of normal laboratory tests (Fig 3B), with pancolitis being worse than either left-sided disease or isolated rectosigmoid disease. Taken together, our results showed that, of patients with only rectosigmoid involvement, 71% had mild disease and 79% had 4 normal laboratory values. In contrast, of patients with pancolitis, 79% were considered to have moderate/severe disease and only 14% (14 of 103 patients) had normal values for all 4 laboratory tests.
Disease severity assessed according to region of disease involvement. Values are frequencies, expressed as percentages of CD (A) and UC (B) participants with mild (light gray bars), moderate (dark gray bars), or severe (black bars) disease for the different sites of bowel involvement. GI indicates gastrointestinal tract.
Frequency of normal laboratory test results. Values are frequencies, expressed as percentages of CD (A) and UC (B) participants with laboratory test results being all normal (light gray bars), 3 normal (dark gray bars), 2 normal (medium gray bars), 1 normal (white bars), or all 4 abnormal (black bars) for the different sites of bowel involvement. GI indicates gastrointestinal tract.
Overall, 41 of 144 children with mild IBD and normal values for all 4 of the laboratory tests evaluated had all clinical information available at the time of diagnosis. The 3 most common presenting features among the subjects with CD were blood in the stools (65%; 13 of 20 patients), abdominal pain (60%; 12 of 20 patients), and fatigue (40%; 8 of 20 patients). Among the UC subjects, hematochezia (90%; 19 of 21 patients), abdominal pain (67%; 14 of 21 patients), and loose stools (33%; 7 of 21 patients) were the most common presenting features. Taking the results together, if blood in the stools is added to the assessment provided by the 4 simple laboratory tests, then only 6% of those with mild IBD (9 of 144 patients) are not identified, which yields a sensitivity for ≥1 abnormal laboratory test and/or hematochezia of 94% in this population. Because of the nature of the study, it was not possible to determine specificity. When subjects with any degree of IBD were included in a similar assessment, the combination of the 4 laboratory tests and a history of blood in the stools resulted in a sensitivity of 98% for the study population.
DISCUSSION
The finding that a significant number of children with IBD have a normal battery of screening laboratory tests at the time of diagnosis has clear implications for primary health care providers. For a child with a history of mild abdominal pain or diarrhea, the presence of normal screening laboratory studies often implicates functional disorders (eg, irritable bowel syndrome) as a cause of symptoms and precludes additional diagnostic testing. Although functional disorders are much more common than IBD, our data show that the presence of normal laboratory test results cannot be relied on as an adequate screening tool to exclude mild IBD. Active IBD is associated with a number of clinical signs and symptoms; if these are present, then additional investigation is warranted. In our study, the most common sign for those with mild IBD was hematochezia, and investigation for children with this problem is warranted even if the laboratory test results are normal. In contrast, children with more-severe IBD only rarely have all 4 of the laboratory tests yielding normal results at presentation.
Failure to diagnose IBD in children with mild symptoms can lead to delayed diagnosis, which can result in more-active disease associated with increased morbidity and complications. For some children eventually diagnosed as having IBD, the time from onset of symptoms to diagnosis of IBD can be long.4,5 Our data did not identify what factors in the presentation of our patients might have prompted additional diagnostic studies for IBD, even in the presence of normal screening laboratory studies. However, many of the children diagnosed as having mild IBD had reports of blood in the stools and possibly other nonspecific complaints (eg, abdominal pain, poor energy, or diarrhea). Therefore, it is clear that physicians must remain suspicious regarding the possibility of IBD in patients with symptoms of intestinal inflammation, irrespective of laboratory findings.
Beattie et al6 reviewed their experience with blood tests in the extensive evaluation of 91 patients who had been suffering for ≥3 months with ≥2 gastrointestinal symptoms of abdominal pain, diarrhea, rectal bleeding, weight loss, or mouth ulceration. Within this group of patients, 39 had either CD (n = 26) or UC (n = 13), and it was concluded that the diagnosis of CD was unlikely if the results of the screening blood tests (hemoglobin level, ESR, albumin level, platelet count, and C-reactive protein [CRP] level) were normal. In their review, CRP was included in addition to the blood tests reviewed in the current study. A recent review of CRP findings in adult CD concluded that use of a threshold 2.5 times the upper limit of the normal CRP range detected 70% of those with moderate or severe disease, although the study did not allow for the separation of mild and nonactive CD.7 Although disease severity was not indicated in the study by Beattie et al,6 it seems that the patients were in the moderate/severe category, not only on the basis of the elevated CRP levels but also because the likelihood of an elevated ESR of 85% for their patients was similar to what we found for the patients in the moderate/severe CD category in the current study. Therefore, we conclude that, even if all of the simple blood tests yield normal results, children should be considered for referral for additional evaluation when there are chronic gastrointestinal complaints, such as hematochezia.
There have been other studies that have evaluated laboratory abnormalities for children and adolescents with IBD.8–13 The sample sizes in those previous studies were also small, ranging between 24 and 100 subjects; in addition, many of those reports did not include variables such as disease severity and/or extent of disease involvement. In a systematic review of anemia that included pediatric and adult studies,11 the general prevalence of anemia in IBD ranged between 10% and 73% in CD and between 9% and 67% in UC. Worse disease severity and younger age were correlated with the frequency of anemia. At diagnosis in our study, we found anemia to be common, with 69% of children with CD (252 of 366 children) and 64% of children with UC (84 of 131 children) being affected. Similar to our data, worse disease severity was correlated directly with frequency of anemia. Weinstein et al12 reviewed laboratory test results for children with newly diagnosed CD (n = 82) or UC (n = 71). They reported that, at the time of presentation, absolute laboratory values for ESR and platelet count were higher in CD than in UC and absolute values for hemoglobin and albumin levels were lower in CD than in UC. With adjustment for disease severity, we could not confirm this finding for severe disease, because at presentation the laboratory values were similar for CD and UC. Furthermore, even at mild and moderate disease severity, there is considerable overlap between laboratory values and clinically it is unlikely that this would be a useful parameter to differentiate subtypes of IBD.
Additional laboratory markers to help diagnose and differentiate subtypes of IBD and to assess IBD disease severity and extent of disease could help in reducing risks and costs to patients, because current evaluation strategies involve labor-intensive, potentially risky, costly methods, including radiologic studies and endoscopic studies with histologic evaluation of specimens, in addition to traditional laboratory testing. Newer and more costly laboratory evaluations have been suggested as ways to discriminate between IBD and other causes of chronic gastrointestinal symptoms, such as irritable bowel syndrome, and to define an individual's IBD. With inflammation of the lining of the gastrointestinal tract being the primary source of inflammation in IBD, detection of a variety of stool markers mostly derived from leukocytes (eg, lactoferrin, elastase, lysozyme, myeloperoxidase, calprotectin, and S100 proteins) has been studied. The noninvasive nature of fecal tests makes them ideal candidates for laboratory markers, but lack of extensive analysis, availability, and costs are drawbacks. Although these tests can have high specificity for inflammation of the intestinal tract, because their source is from leukocytes, they are not specific for IBD, and detection levels may not be equal among the subtypes of IBD.14
Another route for evaluation of laboratory markers has been the evaluation of specific serologic markers for patients with IBD, which has yielded a number of antibodies, including antibodies against neutrophils (atypical, perinuclear, cytoplasmic, DNase-sensitive, antineutrophil antibodies), antibodies against microbial antigens (anti-Saccharomyces cerevisiae antibodies, anti-outer membrane porin C antibodies, anti-I2 antibodies, and antiflagellin antibodies), and antiglycan antibodies.15 The combining of >1 of the markers has produced excellent specificity and good sensitivity16 and may facilitate diagnosis for some patients, but for most patients the diagnosis is suspected without marker use.17 These serologic markers may also define subsets of patients with IBD,18 but, for initial diagnostic tests, it should be kept in mind that they are not available in many individual testing facilities, they are expensive, they do not measure disease activity, and they do not determine the site and extent of disease, the latter of which are used to determine management strategies at the current time. Moreover, for young patients with IBD, it is less likely that serologic tests would be positive,19 which raises the possibility that these antibodies may be secondary phenomenon, may take time to develop, or may not be definable in this subgroup of patients.
Use of a strategy involving only traditional laboratory tests to screen for possible IBD would miss significant numbers of children with primarily mild IBD. However, good clinicians rely on more than just laboratory assessments when making judgments about patients. In particular, the presence of blood in the stools should be a warning sign that a child with normal laboratory results requires additional evaluation. Although clinicians should be reassured that 94% to 98% of children with IBD would be identified with ≥1 abnormal laboratory test or the presence of blood in the stools, clinical suspicion remains critical in the decision-making process, to direct additional diagnostic testing.
Acknowledgments
Financial support for this study was provided by the Ottawa Snowflake Ball, Centocor (Malvern, PA), Reach Out for Youth with Ileitis and Colitis (Melville, NY), and the collaborating institutions.
We are deeply indebted to the following research coordinators, whose efforts greatly facilitated the performance of this study: Ruth Singleton, Patricia Davis, Kathy Grancher, Valerie Grant, Annette Langseder, Anna Zholudev, George Kay, Gail Waltz, Kim Boyer, Shari Huffman, Cathy Williams, Rebecca Abood, Rosemary Nagy, Carol Rudman, Myrna Miller, Vivian Abadom, Janet Trotta, and Laura Defaveri.
Footnotes
- Accepted January 31, 2007.
- Address correspondence to David R. Mack, MD, Children's Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1. E-mail: dmack{at}cheo.on.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
- Copyright © 2007 by the American Academy of Pediatrics
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