- Email: [email protected]
An evaluation of d -xylose absorption measurements in children suspected of having small intestinal disease
Volume 99 Number 2
B r i e f clinical and laboratory observations
24 5
An evaluation of D-xylose absorption measurements in children suspected of having small intestinal disease R. Hill, E. Cutz, G. Cherian, D. G. Gall, and J. R. Hamilton, Toronto, Ont., Canada
EN'I'IqUSIAM for the assessment of D-xylose absorption in patients with gastroenterologic disorders has waxed and waned as various clinical techniques have been developed and subsequently evaluated. A recent study using a relatively large dose of xylose, based on the patient's body surface area, found a close relationship between proximal intestinal mucosal damage and blood concentrations measured one hour later.' We describe a prospective clinical assessment of this same technique in a group of children suspected of having gastroenterologic disease. Our data suggest that the test is of limited value in discriminating between patients with celiac disease, those with less specific mucosal damage, and those with normal small intestinal mucosal structure. MATERIAL
AND METHODS
We studied 44 patients during a 15-month period. Ranging in age from 0.5 to 18 years (mean = 4.6 years), they had been admitted to hospital for the investigation of possible intestinal disease. In each case the clinical and laboratory findings, which included fecal fat balance and microbiologic and roentgenographic data, had led to a decision to undertake a per-oral suction biopsy of the small intestinal mucosa for diagnostic purposes. Before each biopsy was done we carried out a single D-xylose absorption test. The major causes of pancreatic insufficiency in childhood, cystic fibrosis, and Schwachman syndrome had been ruled out in each case. A Carey suction instrument was used to obtain biopsy specimens from the distal duodenal mucosa, just proximal to the ligament of Treitz? Informed consent of a parent or guardian was obtained for each biopsy procedure. Oriented under the dissecting microscope, tissue was fixed in Bouin solution, sectioned, and stained with hematoxylin and eosin for light microscopic study. Well-oriented sections, in which at least three adjacent complete cryptvillus units could be seen, were evaluated by one of us (E. C.) without prior knowledge of the clinical findings. Based primarily on histologic criteria, the patients were assigned to one of three study groups: Group k - N o r m a l duodenal From the Departments" of Pediatrics, Pathology, and Clinical Biochemistry, Hospital for Sick Children, and the University of Toronto. *Reprint address: Division of Gastroenterology, The Hospital for Sick Children, 555 UniversityAve. Toronto, Ontario M5G 1X8.
0022-3476/81/080245 +03500.30/0 9 1981 The C. V. Mosby Co.
mucosal structure. Group II: Structural abnormalities in the duodenal mucosa not diagnostic of celiac disease. Group III: Mucosal structural abnormalities typical of celiac disease? In each case included in this latter group, villus structure was flattened, crypt depth was increased, the surface epithelium was irregular, and the enterocytes had lost their columnar contour. To a varying degree, an increased number of round cells was seen in the lamina propria and lymphocytes were present in the surface epithelial layer. The D-xylose absorption test was conducted using the technique described by Buts et al. 1 After an eight-hour fast each child received D-xylose in a pure form, 14.5 g m / m ~ body surface, given by mouth in a concentration of 10 gm/dl water up to a maximum of 25 gm. Sixty minutes later blood was drawn and serum xylose concentrations measured in duplicate samples by the method of Goodwin? The coefficient of variation for the technique was 8% at a serum concentration of 25 mg/dl. Samples not assayed immediately were frozen at - 5 ~ until assayed. A serum concentration of more than 25 m g / d l was considered normal. None of the patients studied had abnormal renal function, and none was taking a drug known to distort absorption or renal clearance of xylose. All duodenal juices and biopsy specimens were scrutinized for Giardia lamblia. Stools were studied by routine methods for ova, parasites, enteropathogenic bacteria, and, in cases of diarrhea, by electronmicroscopy for viral pathogens. ~ Fat balances were done in 33 patients using four-day collections on a measured fat uptake after 48 hours equilibration; stools were analyzed by the Van de Kamer method? Fat excretion exceeding 10% of intake was considered abnormal except for patients less than 6 months of age, for whom values exceeding 15% were taken as abnormal. RESULTS Of the 44 children studied, biopsy showed normal duodenal mucosal structure in 19 (Group I) and abnormalities typical of celiac disease in 16 (group III). A range of abnormalities was seen in the biopsies of the remaining eight patients (Group II). In one of these eight, an infant, there was profound villus atrophy and hypoplasia of the crypts, a lesion identical to that seen in infants reported previously to have "familial enteropathy"7; another in this
246
Brief clinical and laboratory observations
70"
50
SERUM D-XYLOSE AT 1 HOUR mg/100ml 30
1 0 84
NORMAL
ABNORMAL NON-CELIAC
CELIAC DISEASE
The Journal of Pediatrics June 1981
41.6 _+_ 15.1 (P < 0.001). In aI1 but one of the 19 children with normal biopsies, D-xylose concentrations were normal (Figure). However, of the 17 with a lesion typical of celiac disease, the •-xylose test was normal in five. In the eight children with mucosal lesions not typical of celiac disease, the mean D-xylose concentration, 43.9 _+ 21.7 mg/dl, differed from that of the celiac group (P < 0.01) but not from controls. Abnormal results were seen in only two of these patients, the child with a severe mucosal lesion, apparently the result of familial enteropathy, and another with a mild lesion after apparent enteritis. When quantitative fat balance data, obtained from 14 children with normal mucosal biopsies, 13 with celiac lesions, and six with lesions not typical of celiac disease, were plotted against one-hour D-xylose concentrations, we found a relationship between the two tests (r = 0.40), but fat excretion was normal in three patients with abnormal D-xylose results, and normal D-xylose data were found in three patients with steatorrhea.
DUODENAL MUCOSAL STRUCTURE
Figure. Serum D-xylose data in three groups of patients compared with normal range (< 25 mg/dl).
group had the typical lesion and findings of eosinophilic gastroenteritis; another with Schwachman syndrome, severely malnourished at the time of biopsy, had unexplained focal villus atrophy with a cellular infiltrate in the lamina propria; another child had bacterial overgrowth in the intestinal lumen and stagnant loop syndrome. The other four patients in Group II had symptoms and signs suggestive of celiac disease but their biopsy findings (mild villus shortening, an increased density of round cells in the lamina propria, and a normal epithelium) were not consistent with that diagnosis. The cause of these structural abnormalities in the latter four patients is not clear, but in at least two, symptoms of an acute enteritis had immediately preceded the study. No evidence of an enteric infection, viral, bacterial, or protozoan, was found in stools or biopsies from the 44 children except for the patient with a stagnant loop syndrome and enteric bacterial overgrowth. In each of the 17 children diagnosed by biopsy as having celiac disease, a favorable response to a diet eliminating injurious glutens but allowing cow milk was documented over a six-to 20-month period. In the Group I and Group II patients, observed over a similar period, no findings have emerged to suggest the diagnosis of celiac disease. The mean one-hour serum D-xylose concentration for Group III patients with celiac disease, 21.0 +_ 10.8 mg/dl (mean _+ SD) differed significantly from that in controls,
DISCUSSION In the present study, using the large dose of sugar recently advocated, D-xylose absorption in general reflected the status of the structure of the proximal small intestine as seen in a single suction biopsy. As a group, patients with the severe mucosal lesion caused by celiac disease, had a significantly reduced serum D-xylose concentration compared with those with a variety of other lesions and with those with normal mucosal biopsies. Normal results were obtained in all but one patient with normal mucosa, but the test would have missed the diagnosis in five of 17 cases of celiac disease. Adjustment of the normal range to include all our children with normal biopsies would not have improved the value of the test in detecting the children with celiac disease. The possibility that some of our patients with lesions typical of celiac disease did not actually have celiac disease is very unlikely, since other conditions such as infections and infestations that might have distorted the duodenal mucosa had been ruled out. Although these children have not yet been rechallenged with gluten, as recommended by many authorities for the absolute diagnosis of celiac disease, 8 our experience with the disease '~ strongly supports the specificity of the biopsy findings in our community. In the eight patients with mucosal lesions who did not have celiac disease, the D-xylose test was also of limited discriminatory value. Severe atrophy of the villus structure was associated with an abnormally low one-hour serum xytose concentration in one child, but in the rest of the group with a variety of intestinal lesions, no correla-
Volume 99 Number 2
tion between severity or type of structural defects and xylose data was detected. The lack of strong relationship between one-hour blood D-xylose concentrations and fat excretion, a quantitative measure of absorptive capacity, is in keeping with our failure to show a strong relationship between histologic and xylose data. Our findings support the concept that mucosal structure is an important determinant of xylose absorption. However, even when the dose of the sugar is large and calculated on the basis of the patient's body surface area, we conclude that the D-xylose test is of limited discriminatory value in the diagnosis of young patients suspected of having upper intestinal mucosal disease. We have no explanation for the discrepancy between our findings and those of Buts et al 1 who found very few false-negative results in children with celiac disease. Obviously many variables, in addition to those of proximal intestinal mucosal structure, could influence the serum concentration of D-xylose measured one hour after an oral dose. Our findings do not preclude a use for the test under controlled conditions, for example, in evaluating the response of patients to therapy or to a potential mucosal injury? ~ We thank Mrs. Isobel Badawoy for secretarial assistance.
Brief clinical and laboratory observations
247
REFERENCES 1. Buts J-P, Morin CL, Roy CC, Weber A, and Bonin A:
2. 3.
4. 5.
6.
7.
8. 9.
10.
One-hour blood xylose test: A reliable index of small bowel function, J P~DtATR90:729, 1978. Carey JB: A simplified gastrointestinal biopsy capsule, Gastroenterology 46:550, 1964. Watson AJ, and Wright NA: Morphology and cell kinetics of the jejunal mucosa in untreated patients, Clin Gastroenterol 3:11, 1974. Goodwin JF: Method for simultaneous direct estimations of glucose and xylose in serum, Clin Chem 16:85, 1970. Middleton PJ, Abbott GD, Szymanski MI, Bortolussi R, and Hamilton JR: Orbivirus acute gastroenteritis of infancy, Lancet 1:1241, 1974. Van De Kamer JH, ten Bokkel Huinink H, and Weyers HA: Rapid method of determinations of fat in feces, J Biol Chem 177:347, 1949. Davidson GP, Cutz E, Hamilton JR, and Gall DG: Familial enteropathy: A syndrome of protracted diarrhea from birth, failure to thrive and hypoplastic villous atrophy, Gastroenterology 75:783, 1978. Meevwisse GW: Diagnostic criteria in coeliac disease, Acta Paediatr Scand 59:461, 1970. Hamilton JR, and McNeill LK: Childhood celiac disease: Response of treated patients to a small uniform daily dose of wheat gluten, J P~DtATR81:885, 1972. Morin CL, Weber A, Buts J-P, Roy CC, and Brochu P: One hour blood xylose test in diagnosis of cow's milk protein intolerance, Lancet 1:1102, 1979.
Lactic acidosis in pediatric patients with cancer receiving total parenteral nutrition Russell J. Merritt, M.D., Ph.D.,* Carol E. Ennis, B.S., R.N., Daniel W. Thomas, M.D., and Frank R. Sinatra, M.D., Los Angeles, Calif.
IN A ONE-YEAR PERIOD, we observed lactic acidosis in five oncology patients in association with the use of total parenteral nutrition. There are multiple previous reports of lactic acidosis in patients with cancer, usually leukemia or lymphoma. 1,2 The association with TPN has been noted in two adult patients and has been described in one pediatric patient receiving 10% glucose infusion. :~ ~ The relatively high risk for lactic acidosis in pediatric patients with advanced cancer when receiving TPN has not been previously stressed. From the Nutrition Support Team and Gastroenterology Program, Childrens Hospital of Los Angeles, University of Southern California. *Reprint address: 4650 Sunset Blvd., Los Angeles, CA 9002Z
0022-3476/81/080247 + 04500.40/0 9 1981 The C. V. Mosby Co.
PATIENTS
AND METHODS
The charts of five oncology patients receiving TPN who developed lactic acidosis were reviewed. The T P N solution contained 25% glucose and 4% Freamine (McGaw Laboratories, Irvine, Calif.) with electrolytes, vitamins, Abbreviation used TPN: total parenteral nutrition minerals, and trace elements. Intralipid (Cutter Laboratories, Berkeley, Calif,) was given two or three times weekly. All patients were receiving or had received chemotherapy for their underlying disease. At the time the lactic acidosis developed all patients had a weight for height above the twenty-fifth percentile. Standard methods were used to
I
B r i e f clinical and laboratory observations
24 5
An evaluation of D-xylose absorption measurements in children suspected of having small intestinal disease R. Hill, E. Cutz, G. Cherian, D. G. Gall, and J. R. Hamilton, Toronto, Ont., Canada
EN'I'IqUSIAM for the assessment of D-xylose absorption in patients with gastroenterologic disorders has waxed and waned as various clinical techniques have been developed and subsequently evaluated. A recent study using a relatively large dose of xylose, based on the patient's body surface area, found a close relationship between proximal intestinal mucosal damage and blood concentrations measured one hour later.' We describe a prospective clinical assessment of this same technique in a group of children suspected of having gastroenterologic disease. Our data suggest that the test is of limited value in discriminating between patients with celiac disease, those with less specific mucosal damage, and those with normal small intestinal mucosal structure. MATERIAL
AND METHODS
We studied 44 patients during a 15-month period. Ranging in age from 0.5 to 18 years (mean = 4.6 years), they had been admitted to hospital for the investigation of possible intestinal disease. In each case the clinical and laboratory findings, which included fecal fat balance and microbiologic and roentgenographic data, had led to a decision to undertake a per-oral suction biopsy of the small intestinal mucosa for diagnostic purposes. Before each biopsy was done we carried out a single D-xylose absorption test. The major causes of pancreatic insufficiency in childhood, cystic fibrosis, and Schwachman syndrome had been ruled out in each case. A Carey suction instrument was used to obtain biopsy specimens from the distal duodenal mucosa, just proximal to the ligament of Treitz? Informed consent of a parent or guardian was obtained for each biopsy procedure. Oriented under the dissecting microscope, tissue was fixed in Bouin solution, sectioned, and stained with hematoxylin and eosin for light microscopic study. Well-oriented sections, in which at least three adjacent complete cryptvillus units could be seen, were evaluated by one of us (E. C.) without prior knowledge of the clinical findings. Based primarily on histologic criteria, the patients were assigned to one of three study groups: Group k - N o r m a l duodenal From the Departments" of Pediatrics, Pathology, and Clinical Biochemistry, Hospital for Sick Children, and the University of Toronto. *Reprint address: Division of Gastroenterology, The Hospital for Sick Children, 555 UniversityAve. Toronto, Ontario M5G 1X8.
0022-3476/81/080245 +03500.30/0 9 1981 The C. V. Mosby Co.
mucosal structure. Group II: Structural abnormalities in the duodenal mucosa not diagnostic of celiac disease. Group III: Mucosal structural abnormalities typical of celiac disease? In each case included in this latter group, villus structure was flattened, crypt depth was increased, the surface epithelium was irregular, and the enterocytes had lost their columnar contour. To a varying degree, an increased number of round cells was seen in the lamina propria and lymphocytes were present in the surface epithelial layer. The D-xylose absorption test was conducted using the technique described by Buts et al. 1 After an eight-hour fast each child received D-xylose in a pure form, 14.5 g m / m ~ body surface, given by mouth in a concentration of 10 gm/dl water up to a maximum of 25 gm. Sixty minutes later blood was drawn and serum xylose concentrations measured in duplicate samples by the method of Goodwin? The coefficient of variation for the technique was 8% at a serum concentration of 25 mg/dl. Samples not assayed immediately were frozen at - 5 ~ until assayed. A serum concentration of more than 25 m g / d l was considered normal. None of the patients studied had abnormal renal function, and none was taking a drug known to distort absorption or renal clearance of xylose. All duodenal juices and biopsy specimens were scrutinized for Giardia lamblia. Stools were studied by routine methods for ova, parasites, enteropathogenic bacteria, and, in cases of diarrhea, by electronmicroscopy for viral pathogens. ~ Fat balances were done in 33 patients using four-day collections on a measured fat uptake after 48 hours equilibration; stools were analyzed by the Van de Kamer method? Fat excretion exceeding 10% of intake was considered abnormal except for patients less than 6 months of age, for whom values exceeding 15% were taken as abnormal. RESULTS Of the 44 children studied, biopsy showed normal duodenal mucosal structure in 19 (Group I) and abnormalities typical of celiac disease in 16 (group III). A range of abnormalities was seen in the biopsies of the remaining eight patients (Group II). In one of these eight, an infant, there was profound villus atrophy and hypoplasia of the crypts, a lesion identical to that seen in infants reported previously to have "familial enteropathy"7; another in this
246
Brief clinical and laboratory observations
70"
50
SERUM D-XYLOSE AT 1 HOUR mg/100ml 30
1 0 84
NORMAL
ABNORMAL NON-CELIAC
CELIAC DISEASE
The Journal of Pediatrics June 1981
41.6 _+_ 15.1 (P < 0.001). In aI1 but one of the 19 children with normal biopsies, D-xylose concentrations were normal (Figure). However, of the 17 with a lesion typical of celiac disease, the •-xylose test was normal in five. In the eight children with mucosal lesions not typical of celiac disease, the mean D-xylose concentration, 43.9 _+ 21.7 mg/dl, differed from that of the celiac group (P < 0.01) but not from controls. Abnormal results were seen in only two of these patients, the child with a severe mucosal lesion, apparently the result of familial enteropathy, and another with a mild lesion after apparent enteritis. When quantitative fat balance data, obtained from 14 children with normal mucosal biopsies, 13 with celiac lesions, and six with lesions not typical of celiac disease, were plotted against one-hour D-xylose concentrations, we found a relationship between the two tests (r = 0.40), but fat excretion was normal in three patients with abnormal D-xylose results, and normal D-xylose data were found in three patients with steatorrhea.
DUODENAL MUCOSAL STRUCTURE
Figure. Serum D-xylose data in three groups of patients compared with normal range (< 25 mg/dl).
group had the typical lesion and findings of eosinophilic gastroenteritis; another with Schwachman syndrome, severely malnourished at the time of biopsy, had unexplained focal villus atrophy with a cellular infiltrate in the lamina propria; another child had bacterial overgrowth in the intestinal lumen and stagnant loop syndrome. The other four patients in Group II had symptoms and signs suggestive of celiac disease but their biopsy findings (mild villus shortening, an increased density of round cells in the lamina propria, and a normal epithelium) were not consistent with that diagnosis. The cause of these structural abnormalities in the latter four patients is not clear, but in at least two, symptoms of an acute enteritis had immediately preceded the study. No evidence of an enteric infection, viral, bacterial, or protozoan, was found in stools or biopsies from the 44 children except for the patient with a stagnant loop syndrome and enteric bacterial overgrowth. In each of the 17 children diagnosed by biopsy as having celiac disease, a favorable response to a diet eliminating injurious glutens but allowing cow milk was documented over a six-to 20-month period. In the Group I and Group II patients, observed over a similar period, no findings have emerged to suggest the diagnosis of celiac disease. The mean one-hour serum D-xylose concentration for Group III patients with celiac disease, 21.0 +_ 10.8 mg/dl (mean _+ SD) differed significantly from that in controls,
DISCUSSION In the present study, using the large dose of sugar recently advocated, D-xylose absorption in general reflected the status of the structure of the proximal small intestine as seen in a single suction biopsy. As a group, patients with the severe mucosal lesion caused by celiac disease, had a significantly reduced serum D-xylose concentration compared with those with a variety of other lesions and with those with normal mucosal biopsies. Normal results were obtained in all but one patient with normal mucosa, but the test would have missed the diagnosis in five of 17 cases of celiac disease. Adjustment of the normal range to include all our children with normal biopsies would not have improved the value of the test in detecting the children with celiac disease. The possibility that some of our patients with lesions typical of celiac disease did not actually have celiac disease is very unlikely, since other conditions such as infections and infestations that might have distorted the duodenal mucosa had been ruled out. Although these children have not yet been rechallenged with gluten, as recommended by many authorities for the absolute diagnosis of celiac disease, 8 our experience with the disease '~ strongly supports the specificity of the biopsy findings in our community. In the eight patients with mucosal lesions who did not have celiac disease, the D-xylose test was also of limited discriminatory value. Severe atrophy of the villus structure was associated with an abnormally low one-hour serum xytose concentration in one child, but in the rest of the group with a variety of intestinal lesions, no correla-
Volume 99 Number 2
tion between severity or type of structural defects and xylose data was detected. The lack of strong relationship between one-hour blood D-xylose concentrations and fat excretion, a quantitative measure of absorptive capacity, is in keeping with our failure to show a strong relationship between histologic and xylose data. Our findings support the concept that mucosal structure is an important determinant of xylose absorption. However, even when the dose of the sugar is large and calculated on the basis of the patient's body surface area, we conclude that the D-xylose test is of limited discriminatory value in the diagnosis of young patients suspected of having upper intestinal mucosal disease. We have no explanation for the discrepancy between our findings and those of Buts et al 1 who found very few false-negative results in children with celiac disease. Obviously many variables, in addition to those of proximal intestinal mucosal structure, could influence the serum concentration of D-xylose measured one hour after an oral dose. Our findings do not preclude a use for the test under controlled conditions, for example, in evaluating the response of patients to therapy or to a potential mucosal injury? ~ We thank Mrs. Isobel Badawoy for secretarial assistance.
Brief clinical and laboratory observations
247
REFERENCES 1. Buts J-P, Morin CL, Roy CC, Weber A, and Bonin A:
2. 3.
4. 5.
6.
7.
8. 9.
10.
One-hour blood xylose test: A reliable index of small bowel function, J P~DtATR90:729, 1978. Carey JB: A simplified gastrointestinal biopsy capsule, Gastroenterology 46:550, 1964. Watson AJ, and Wright NA: Morphology and cell kinetics of the jejunal mucosa in untreated patients, Clin Gastroenterol 3:11, 1974. Goodwin JF: Method for simultaneous direct estimations of glucose and xylose in serum, Clin Chem 16:85, 1970. Middleton PJ, Abbott GD, Szymanski MI, Bortolussi R, and Hamilton JR: Orbivirus acute gastroenteritis of infancy, Lancet 1:1241, 1974. Van De Kamer JH, ten Bokkel Huinink H, and Weyers HA: Rapid method of determinations of fat in feces, J Biol Chem 177:347, 1949. Davidson GP, Cutz E, Hamilton JR, and Gall DG: Familial enteropathy: A syndrome of protracted diarrhea from birth, failure to thrive and hypoplastic villous atrophy, Gastroenterology 75:783, 1978. Meevwisse GW: Diagnostic criteria in coeliac disease, Acta Paediatr Scand 59:461, 1970. Hamilton JR, and McNeill LK: Childhood celiac disease: Response of treated patients to a small uniform daily dose of wheat gluten, J P~DtATR81:885, 1972. Morin CL, Weber A, Buts J-P, Roy CC, and Brochu P: One hour blood xylose test in diagnosis of cow's milk protein intolerance, Lancet 1:1102, 1979.
Lactic acidosis in pediatric patients with cancer receiving total parenteral nutrition Russell J. Merritt, M.D., Ph.D.,* Carol E. Ennis, B.S., R.N., Daniel W. Thomas, M.D., and Frank R. Sinatra, M.D., Los Angeles, Calif.
IN A ONE-YEAR PERIOD, we observed lactic acidosis in five oncology patients in association with the use of total parenteral nutrition. There are multiple previous reports of lactic acidosis in patients with cancer, usually leukemia or lymphoma. 1,2 The association with TPN has been noted in two adult patients and has been described in one pediatric patient receiving 10% glucose infusion. :~ ~ The relatively high risk for lactic acidosis in pediatric patients with advanced cancer when receiving TPN has not been previously stressed. From the Nutrition Support Team and Gastroenterology Program, Childrens Hospital of Los Angeles, University of Southern California. *Reprint address: 4650 Sunset Blvd., Los Angeles, CA 9002Z
0022-3476/81/080247 + 04500.40/0 9 1981 The C. V. Mosby Co.
PATIENTS
AND METHODS
The charts of five oncology patients receiving TPN who developed lactic acidosis were reviewed. The T P N solution contained 25% glucose and 4% Freamine (McGaw Laboratories, Irvine, Calif.) with electrolytes, vitamins, Abbreviation used TPN: total parenteral nutrition minerals, and trace elements. Intralipid (Cutter Laboratories, Berkeley, Calif,) was given two or three times weekly. All patients were receiving or had received chemotherapy for their underlying disease. At the time the lactic acidosis developed all patients had a weight for height above the twenty-fifth percentile. Standard methods were used to
I