Pfefferkorn, Marian D.; Fitzgerald, Joseph F.; Croffie, Joseph M.; Gupta, Sandeep K.; Corkins, Mark R.; Molleston, Jean P.
Low lactase activity is the most common of all small intestinal disaccharidase enzyme deficiencies (1). Lactase enzyme levels are usually high at birth and decrease after weaning (2,3). Congenital hypolactasia is extremely rare, whereas late-onset lactose malabsorption occurs in as many as 100% of Asians, 81% of blacks, and 24% of whites, and may manifest as early as 5 years of age (4). Lactase deficiency is common in adults with chronic inflammatory bowel disease (IBD) (5–7); hence, lactose-free diets are frequently prescribed to newly diagnosed patients with Crohn disease (CD) and ulcerative colitis (UC). As many as 80% of gastroenterologists surveyed indicated that they have recommended avoidance of milk and milk products to patients with UC (8). It has been presumed that lactase deficiency also occurs in children with IBD because of the results of studies in adult patients, but there is a paucity of available data on this issue in pediatric patients. Our primary aim was to determine the prevalence of lactase deficiency in pediatric patients with IBD. A second aim was to correlate lactase activity levels with inflammatory changes in the proximal bowel mucosa in patients with IBD.
MATERIALS AND METHODS
Pediatric and adolescent patients with symptoms suggestive of IBD and patients previously diagnosed with CD and UC who were being evaluated at Riley Children's Hospital for suspected active disease were identified. Their symptoms included abdominal pain, vomiting, weight loss, and/or diarrhea. Medical records were reviewed from January 1994 to December 2000, to identify patients who had had biopsy specimens taken from the proximal small bowel (duodenum and/or proximal jejunum) for measurement of lactase activity during endoscopic examinations of the upper and lower gastrointestinal tracts. Age- and gender-matched controls were chosen randomly from a list of patients evaluated during the same period for chronic abdominal pain. Institutional review board documentation was not required at the time this retrospective study was initiated.
Intestinal Mucosal Biopsy
Mucosal pinch biopsy specimens were taken from the third portion of the duodenum or proximal jejunum during endoscopic evaluation of the upper digestive tract. These specimens were immediately placed in dry ice and sent to a reference laboratory for determination of disaccharidase enzyme activities. Additional biopsy specimens were taken from the proximal small bowel and other affected areas for histologic examination. These specimens were oriented on filter paper and transported in formalin to the surgical pathology laboratory.
Lactase activity was determined by the method of Dahlqvist (9) at one of two reference laboratories: State University of New York (Buffalo, NY, U.S.A.) and JOLI Diagnostic Inc (Williamsville, NY, U.S.A). Enzymatic activities are reported as micromoles of lactose hydrolyzed per minute at 37°C per gram of protein.
Biopsy specimens were stained with hematoxylin–eosin. The degree of inflammation was simultaneously assessed by two board-certified pediatric pathologists as mild, moderate, or severe based on the amount of acute or chronic cellular inflammatory infiltrate of the lamina propria. Villus architecture, gland branching, crypt shortfall, cryptitis, and the presence or absence of granulomas were also described.
The z-test analysis was used to determine if there was a difference in the frequency of lactase deficiency in patients with IBD compared with non-IBD control patients with abdominal pain, and in patients with UC versus CD. The Kruskall-Wallis one-way analysis of variance was used to determine the relation between age and the occurrence of lactase deficiency in patients with IBD compared with controls. The Mann-Whitney rank sum test was used to determine a difference in age between the patients with IBD compared with controls and to determine the relation between 1) lactase deficiency and the presence of duodenal inflammation, and 2) lactase activity level and degree of inflammation in extraduodenal sites: esophagus, stomach, proximal jejunum, terminal ileum, colon, and rectum.
One hundred twelve symptomatic patients with IBD had lactase activity determined: 60 (54%) males, 103 (92%) whites, and 9 (8%) blacks. Seventy-nine (71%) had CD, and 33 (29%) had UC, with ages ranging from 5.6 years to 18.3 years and 1.8 years to 16.8 years, respectively. The mean age of all IBD patients was 12.7 years. Nine patients with CD and seven with UC underwent endoscopic reevaluation with mucosal biopsy during this period, yielding 129 samples.
The age- and gender-matched control group consisted of 112 patients evaluated for abdominal pain. Their ages ranged from 1.9 years to 18.7 years (mean, 12.4 years) and were similar to the IBD group (P = 0.528). The diagnoses after evaluation are shown in Table 1.
Twenty-nine of 79 patients with CD (37%) and 16 of 33 with UC (48%), or a total of 45 of 112 (40%) of all patients with IBD, had low lactase activity levels (< 15 μM/min/gm). There was no significant difference in the frequency of lactase deficiency in patients with CD compared with patients with UC (P = 0.344). Thirty-four of 112 (30%) non-IBD control patients with abdominal pain were found to have lactase deficiency. Although lactase deficiency was more frequently observed in IBD patients than in controls, the difference was not statistically significant (P = 0.162). There was no significant difference in age and lactase activity levels between IBD patients and control patients (P = 0.854). Three of the 11 patients who underwent repeat endoscopy during this period, who initially had normal lactase activities, developed lactase deficiency on follow-up. One was a 13.3-year-old white American with moderately active UC whose lactase activity decreased from 17.7 μM/min/gm to 7.4 μM/min/gm at 14.2 years, despite normal duodenal biopsy results. The second patient was a 10.3-year-old white American with CD and normal lactase activity initially who developed lactase deficiency in the absence of duodenal inflammation 1 year later. The third patient was a 7.9-year-old white American with CD whose lactase activity decreased from 42 μM/min/gm to 2.2 μM/min/gm at 9.8 years. The latter was associated with severe duodenal inflammation and villus atrophy. Three white American patients with UC, aged 5, 9, and 16 years, and two 14-year-old white American patients with CD had persistent lactase deficiency on follow-up. No patient with lactase deficiency developed lactase sufficiency on follow-up.
Low lactase in the IBD group ranged from 0 to 14.2 μM/min/gm (mean, 6.5 μM/min/gm) (Fig. 1). Four had alactasia. Seven of nine black patients and 38 of 103 white patients had low lactase activity levels, giving a prevalence of 78% and 37%, respectively. All of the nine blacks from the control group were lactase deficient (lactase = 0–7.5 μM/min/gm) compared with 25 of 103 (24%) of whites.
None of the non-IBD control patients with lactase deficiency had any duodenal villous blunting. Thirty (67%) of 45 IBD patients with low lactase had normal duodenal histology, whereas 15 of 45 (33%) had mucosal changes in the duodenum, varying from mild to severe inflammation. Of the 15 patients with duodenal inflammation, 9 had CD and 6 had UC. Only 2 of these 15 patients, a 9.8-year-old white patient with CD and an 11.9-year-old black patient with CD, had duodenal villus blunting. Among patients with IBD and normal lactase, 55 of 67 (82%) had normal duodenal histology, and 12 of 67 (18%) had mild to severe inflammation. Three patients in the latter group had villus atrophy: one with UC and two with CD. The presence of duodenal inflammation did not significantly differ between lactase-deficient and -sufficient IBD patients (P = 0.068). The degree of inflammation in extraduodenal sites was not significantly different between lactase-deficient and -sufficient patients with IBD (P = 0.213).
Symptoms of lactose malabsorption include diarrhea, nausea, vomiting, abdominal cramps, distension, and pain (10,11), which are also commonly experienced by patients with active IBD. It is imperative to differentiate lactose malabsorption from active IBD, as the management of these differ. It is clinically relevant to know whether lactose malabsorption is contributing to the symptoms of the patient with IBD.
Lactose malabsorption can be diagnosed by indirect methods, including the oral lactose tolerance test, breath carbon dioxide test using 13C- or 14C-labeled lactose, and the breath hydrogen test (1,4). The oral lactose tolerance test was found to have a sensitivity of 76% and a specificity of 96% in adults (12). However, it is unpleasant to perform in children because it requires taking blood samples for the measurement of glucose at least five times over a 3-hour period after the ingestion of the lactose load. The breath 14CO2 test is more sensitive but has not been commonly used in children because of the potential radiation hazard. The most simple and reliable test is the breath hydrogen test, which can be safely performed in children. In adults, the sensitivity and specificity of the breath hydrogen test was reported to be 100% (12), but this was not reproduced in studies of infants and children with chronic diarrhea, where the sensitivities and specificities were only 75% to 77% and 41% to 86%, respectively (13,14).
Direct measurement of lactase activity in small bowel biopsy specimens establishes lactase deficiency. There are concerns, however, that lactase deficiency secondary to mucosal injury may be focal or patchy, and a falsely normal lactase activity may be found (4). Heitlinger et al. (15) reported that lactase activities were inversely correlated with the degree of mucosal injury among 798 pediatric patients studied. Our group similarly found that decreased lactase activities were commensurate with the degree of villus atrophy in pediatric patients with diarrhea (16). Surprisingly, we did not find such a relation with lactase activities and degree of mucosal inflammation in the proximal intestines of our patients with IBD. Sixty-seven percent of the patients with lactase deficiency had normal duodenal biopsy results, without villus atrophy. Of the remaining 33% of patients with lactase deficiency, all had duodenal inflammation, but only two had duodenal villus blunting. Conversely, 18% of patients with IBD and normal lactase activities had mild to severe inflammation in the duodenum, three of whom had villus blunting. Thus, it appears that the occurrence of lactase deficiency in pediatric patients with IBD does not correlate with proximal small bowel inflammation. The severity of mucosal inflammation found elsewhere in the gastrointestinal tract also did not differ between the lactase-deficient and the -sufficient patients. There was no significant difference in the frequency of lactase deficiency in patients with UC compared with those with CD, and in IBD patients compared with a population of patients with chronic abdominal pain. These findings were also observed by Kirschner et al. (17), who performed the lactose breath hydrogen test to determine lactose malabsorption.
Complete avoidance of milk and milk products will obviate the symptoms of lactose malabsorption, although decreasing the milk intake may also prevent discomfort (4). Patients with IBD, especially CD, usually have a compromised nutritional status and a greater risk for osteopenia, as shown in studies evaluating bone mineral density using dual energy x-ray absorptiometry (18,19). In lieu of milk restriction, it is better to supplement lactase-deficient IBD patients with commercially available lactase preparations that are bacterial- or yeast-derived β-galactosidases (20). Yogurt, which contains endogenous β-galactosidase, is a useful alternate source of calcium and calories (21).
We would like to address the limitations of our data. First, we only reported symptomatic IBD patients who had lactase activity levels measured. There may be asymptomatic IBD patients with lactase deficiency who have not undergone testing. Although the latter would affect the prevalence, it would not result in changes in management as far as lactase supplementation. Second, because this was a retrospective study, the response of lactase-deficient IBD patients and patients with abdominal pain to lactose-hydrolyzed milk and foods was not documented. In lactase-deficient patients previously studied by our group (16), 81% responded favorably to lactase supplementation with resolution of abdominal pain and/or diarrhea. Finally, we were unable to show a difference in the frequency of lactase deficiency in IBD patients compared with patients with chronic abdominal pain. It is known that lactose intolerance is one of the causes of recurrent abdominal pain (10,11), and 30% of our control group did have low lactase activities. This percentage is similar to a group of white patients evaluated for diarrhea and irritable bowel syndrome, where 24.6% of patients older than 5 years (with normal jejunal biopsy results) were found to have low lactase activities (22). The ideal control population would have been random sampling of a general pediatric population in the United States, where the prevalence of lactose intolerance is 24% in white patients (4). We are unaware of any large studies investigating the prevalence of lactose intolerance in children without gastrointestinal symptoms. A smaller study of patients with chronic upper airway disease showed that 5 of 28 patients (18%) had lactase deficiency, based on measurement of small bowel lactase activity and the lactose breath hydrogen test (23).
In conclusion, more than one third of pediatric patients with IBD have lactase deficiency. Lactase deficiency appears to be more frequent in IBD (40%) than in patients with abdominal pain (30%), although this observation is not statistically significant. The majority of IBD patients with lactase deficiency have normal duodenal biopsy results without villus atrophy. Avoidance of a lactose-containing diet should not be routinely recommended to pediatric patients with IBD until evaluation for lactase deficiency or lactose intolerance is performed. We recommend that small bowel biopsy specimens be obtained for measurement of lactase activity during initial endoscopic evaluation of patients suspected to have IBD. Having this information will influence the decision to recommend lactase supplementation. Repeat measurement of lactase activity in the deficient patient, either by small bowel biopsy or the breath hydrogen test, can be considered during follow-up of symptomatic patients.
We thank Vicki Haviland for assistance in the preparation of the manuscript.
1. Goldberg DM. The enzymology of intestinal disease. Clin Biochem 1987; 20:63–72.
2. Flatz G, Rotthauwe HW. The human lactose polymorphism: Physiology and genetics of lactose absorption and malabsorption. Prog Med Genet 1977; 2:205–49.
3. Kretchmer N. Memorial lecture: Lactose and lactase—A historical perspective. Gastroenterology 1971; 61:805–13.
4. Buller HA, Grand RJ. Lactose intolerance. Annu Rev Med 1990; 41:141–8.
5. Gudmand-Hoyer E, Binder V, Soltoft J. The small intestinal disaccharidase activity in ulcerative colitis. Scand J Gastroenterol 1975; 10:209–12.
6. Arvanitakis C. Abnormalities of jejunal mucosal enzymes in ulcerative colitis and Crohn's disease. Digestion 1979; 19:259–66.
7. Dunne WT, Cooke WT, Allan RN. Enzymatic and morphometric evidence for Crohn's disease as a diffuse lesion of the gastrointestinal tract. Gut 1977; 18:290–4.
8. Bernstein CN, Ament M, Artinian L, et al. Milk tolerance in adults with ulcerative colitis. Am J Gastroenterol 1994; 89:872–7.
9. Dahlqvist A. Assays of intestinal disaccharidases. Anal Biochem 1968; 22:99–107.
10. Barr RG, Levine MD, Watkins JB. Recurrent abdominal pain of childhood due to lactose intolerance: A prospective study. N Engl J Med 1979; 300:1449–52.
11. Liebman WM. Recurrent abdominal pain in children: Lactose and sucrose intolerance—A prospective study. Pediatrics 1979; 64:43–5.
12. Newcomer AD, McGill DB, Thomas PJ, et al. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med 1975; 293;1232–5.
13. Maffei HVL, Metz G, Bampoe V, et al. Lactose intolerance, detected by the breath hydrogen test, in infants and children with chronic diarrhea. Arch Dis Child 1977; 52:766–71.
14. Hyams JS, Stafford RJ, Grand RJ, et al. Correlation of lactose breath hydrogen test, intestinal morphology, and lactase activity in young children. J Pediatr 1980; 97:609–12.
15. Heitlinger LA, Rossi TM, Lee P-C, et al. Human intestinal disaccharidase activities: Correlations with age, biopsy technique, and degree of villus atrophy. J Pediatr Gastroenterol Nutr 1991; 12:204–8.
16. Gupta SK, Chong SKF, Fitzgerald JF. Disaccharidase activities in children: Normal values and comparison based on symptoms and histologic changes. J Pediatr Gastroenterol Nutr 1999; 28:246–51.
17. Kirschner BS, DeFavaro MV, Jensen W. Lactose malabsorption in children and adolescents with inflammatory bowel disease. Gastroenterology 1981; 81:829–32.
18. Gokhale R, Favus M, Karrison T, et al. Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology 1998; 114:902–11.
19. Semeao E, Abbas J, Stouffer N, et al. Risk factors for low bone mineral density in children and young adults with Crohn's disease. J Pediatr 1999; 135:593–600.
20. Newcomer AD, McGill DB. Clinical importance of lactase deficiency. N Engl J Med 1984; 310:42–3.
21. Kolars JC, Levitt MD, Aouji M, et al. Yogurt-an autodigesting source of lactose. N Engl J Med 1984; 310:1–3.
22. Lebenthal E, Antonowicz I, Shwachman H. Correlation of lactase activity, lactose tolerance and milk consumption in different age groups. Am J Clin Nutr 1975; 28:595–600.
23. Forget P, Lombet J, Grandfils C, et al. Lactase insufficiency revisited. J Pediatr Gastroenterol Nutr 1985; 4:868–72.
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