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Carbohydrate intolerance in infants with diarrhea
760
November, I971 T h e ] o u r n a l of P E D I A T R I C S
Carbohydrate intolerance "infants ith diarrhea In infants hospitalized with severe diarrhea, lactose intolerance was considered to be present when the stools had a carbohydrate content greater than 0.25 per cent, and~or a p H of less than 6.0. By these criteria, 255 or 77 per cent of 332 infants had lactose intolerance. All but 2 of the 77 lactose-tolerant patients recovered within 3 weeks while receiving a milk formula, whereas 111 of 195 with mild intolerance ( ~ 30 per cent positive stools) and 13 of 60 with severe lactose intolerance ( ~ 30 per cent positive stoo{s) recovered while receiving a milk formula. Diarrhea lasted more than 3 weeks in 27 per cent o[ those with mild and in 62 per cent of those with untreated severe intolerance; with dietary treatment a prompt [avorable response was elicited. Lactose intolerance was positively correlated with increasing severity of malnutrition but not with previous episodes of gastroenteritis, the presence of enteropathogens, or associated infections. Antibiotic therapy increased the stool pH toward alkaline but did not modify the excretion of carbohydrates.
Fima Lifshitz, M.D.,* Pedro Coello-Ramirez, M.D., Guillermo Gutierrez-Topete, M.D., and Maria Cinta Cornado-Cornet, Q.F.B. MEXICO
C I T Y t M E X I C O ~ AND B A L T I M O R E
T~E INFLUZ~C~ OF carbohydrates on the pathogenesis of diarrhea has been studied since the early part of this century, z In 1921, Howland'-' classified infants with diarrhea into those who had congenital difFrom the Hospital de Pediatria, Centro Medico Nacional, I.M.S.S., the Department of Pediatrics, University of Maryland Hospital, and Rosewood State Hospital. Read in part before the I V Congreso de Pediatria de Ias Naciones Latinas, Guadalajara, ]al, Mexico, December 9, 1968. ~Reprlnt address: Department of Pediatrics, University of Ma'ryland Hospital, Baltimore, Md. 21201.
VoI. 79~ No. 5, pp. 760-767
AND O W I N G S
M I L L S ~ MD.
ficu!ties with ingested carbohydrates, those with a temporary alteration following gastroenteritis, and those with prolonged carbohydrate intolerance. Subsequently, it was shown that diarrhea resulted from a deficiency of the enzymes necessary for hydrolysis of dietary disaccharides and that improvement occurred only after the offending carbohydrate was eliminated from the diet? -s The evaluation of the capacity of patients with diarrhea to tolerate carbohydrates has varied from clinical observations following
Volume 79 Number 5
Carbohydrate intolerance with diarrhea
empirical dietary changes to the measurements of blood sugar levels after the oral administration of-disaceharides and their component monosaecharides?, 9 In addition, quantification of organic acids and carbohydrates in feces*, 10, n and measurements of disaccharidase activity in homogenates of intestinal mucosa ~-~, 12, 13 have been reported. These techniques, although accurate, are not applicable for general clinical use. The purpose of this report is to describe the results of the use of simple bedside methods to determine reducing substances 1. and p H in multiple fresh stool specimens of 332 infants with diarrhea. These tests were useful in detecting a reduced capacity to tolerate lactose in 77 per cent of these patients. MATERIALS
AND METHODS
From December 1, 1967, to January 30, 1969, 332 of 403 infants with severe diarrhea admitted to one of the diarrhea wards of the Hospital de Pediatria, Centro Medico Nacional, I.M.S.S., were studied during the acute stage of their illness. At the time of admission, the mean age of the patients was 5.8 _+ 1.8 months, mean body weight, 4.66 _+ 0.72 Kg., and mean length 59.8 + 2.3 cm. (_+ 95% confidence intervals). In only 32 infants was the body weight within normal limits of age and length for Mexican infants; in all others there was malnutrition of varying degrees. All 332 patients were dehydrated and had metabolic acidosis and electrolyte deficits; 191 had had previous episodes of gastroenteritis. The duration of the diarrhea prior to admission varied from 2 days to 3 months. Enteropathogens (E. coli, Shigella, Salmonella) were cultured from the stools of 126 infants, Entamoeba histolytica of 5, and Giardia lamblia of 12. Ninety patients had infections in addition to diarrhea. The patients had been fed milk prior to admission to the hospital. After admission, all were given fluids and electrolytes intravenously. Milk feedings were begun 8 to 24 hours after admission and by 36 hours, the infants were receiving 150 ml. per kilogram
76 1
of body weight per day of a full-strength milk formula containing 4.5 per cent lactose (20 cal. per 30 ml.). Milk was given throughout the course to 204 infants; a formula containing a different carbohydrate was substituted after varying intervals of diarrhea in 128 patients. The decision to initiate dietary therapy varied with the duration and severity of the illness and the presence of stools with an acid p H and carbohydrates. All 67 patients who had diarrhea for more than 3 weeks were given dietary treatment. In addition, 17 and 44 infants of the group who excreted acid stools and carbohydrates were arbitrarily selected for treatment during the first week, and between 1 and 3 weeks of diarrhea, respectively. Treatment was begun with a lactose-free diet, followed by a disaccharide-free, then a carbohydrate-free diet if the diarrhea persisted.15, a6 Antibiotics were given to 134 patients; indications for antibiotic therapy were often related to the presence of enteropathogens in the stools or other nonenteric infections. Two or 3 fresh stools per day were collected throughout the diarrheal period and immediately assayed for pH, reducing substances, and glucose. The fecal p H was determined directly from the stool water, and the concentrations of carbohydrates were measured after a 1:2 dilution? 4 Urinary contamination of the specimens was avoided by using a urine collector. Reducing substances in the feces were determined by Clinitest tablets, and glucose and p H by Combistix (Ames Co., Division Miles Labs, Elkhart, Ind.). The p H of some stool samples was simultaneously determined with a glass electrode (Beckman Expanded Scale p H Meter, Model 76, Beckman Instruments Inc., Fullerton, Calif.). The correlation coefficient between both methods for measurements of fecal p H was r = 0.94 (Y = 0.588 + 0.932x; Y --= Potentiometer, X -=- Combistix) ; the estimated variance of the slope was 0.0048 and of the intercept 0.0208. Therefore, all p H values used in the analyses were those obtained by use of Combistix. There were 3,450 liquid stool samples
762
Lifshitz et al.
P
The Journal of Pediatrics November 1971
P
P < o.ool
OOO
t)
>6.0
6,0 pH
<6.0
0.25 %
NEG
~>0 . 5 0 %
REDUCING SUBSTANCES
NEG
+
++
GLUCOSE
Fig. 1. pH, reducing substances, and glucose in diarrheal stools. The pH and carbohydrate content of stools from 77 patients who tolerated lactose ( | ) , are compared with those of 195 patients with mild lactose intolerance ( D ) , and with those of 60 patients with severe lactose intolerance (~-~). The mean number of stools excreted per day, per patient during the study period was similar for the 3 groups of patients: 5.36, 6.08, and 6.12, respectively. The mean intakes of milk formula for the 3 groups of patients were similar: 138, 137, and 143 ml. per kilogram per day, respectively.
analyzed for pH, 3,427 for reducing substances, and 3,401 for glucose, from 332 patients with diarrhea while receiving a milk formula. The mean number of stools analyzed per day, per patient was 2.31, and the mean number of stools excreted per day was 5.88. A patient with diarrhea was considered to have lactose intolerance if, while receiving a milk formula, he excreted stools with reducing substances or glucose in concentrations above 0.25 per cent and 1+, respectively, and/or with a p H of less than 6.0. The period of diarrhea during which the patients manifested lactose intolerance varied: (a) initial stage: within 72 hours after beginning milk formula, (b) later stage: after the first week of hospitalization, and (c) no specific pattern: intermittently, throughout the course of diarrhea. The severity of lactose intolerance was assessed by the proportion of liquid stools containing reducing substances and/or glucose, and with a pH of less than 6.0 while the patient received milk formula. Lactose intolerance was considered to be mild when less than 30 per cent of the stool samples were positive. The intolerance was defined
as severe when more than 30 per cent had positive tests. Lactose intolerance was considered to be specific for this disaccharide when improvement of diarrhea followed the elimination of lactose from the diet. The intolerance was considered to be generalized to all disaccharides or to all monosaccharides, when the improvement occurred after the institution of disaccharide-free or carbohydrate-free feedings, respectively. The results of the stool analyses were compared with those of (a) 213 normal stools from 20 infants who did not have diarrhea (the mean age, weight, and length were similar to those of patients with diarrhea), (b) 443 fecal samples of 114 milk fed infants following the first 3 days after recovery from diarrhea, and (c) 269 stools of 54 patients with diarrhea who were fasting. There were no significant differences in the parameters measured in these 3 groups; thus all the data were combined as control material. Statistical treatment of the data was performed by chi square tests comparing the differences between proportions on a twovariables classification. 17
Volume 79 Number 5
Carbohydrate intolerance with diarrhea
763
100 90 I.Ill
-l-I1: rl,{t
70,
I I---
{/}
idl
t-.c[
30-
h
o
20I001
v
<7
7-21
>21
DAYS OF DIARRHEA Fig, 2. Duration of diarrhea in patients receiving milk formula. The percentages of patients who persisted with loose stools at different time intervals, corrected for the number of infants who died or who were removed for dietary therapy at each interval. Of 77 lactose-tolerant patients (@ O ) , 3 died before the diarrhea ceased, and 2 were given dietary treatment after 21 days. Of 195 infants with mild lactose intolerance (x x), 3 died before recovery, and 81 were given dietary treatment. Of 60 patients with severe lactose intolerance ([-] [[]), 2 died, and 45 required dietary treatment. The proportions of patients with persistent diarrhea in each group were significantly different from one another (P ( 0 . 0 1 ) .
RESULTS
During the period of milk intake, 27.4 per cent of the liquid stools from the diarrhea group were acid, 17.4 per cent contained reducing substances, and 10.3 per cent had glucose. In contrast, 3.7 per cent of the control specimens had a p H less than 6.0, and less than 1.0 per cent of the specimens contained carbohydrates (P < 0.01). The presence of carbohydrates in the stools was positively correlated with the fecal pH. Carbohydrates were found in 57.2 per cent of the stools with p H < 6.0, whereas only 38.4 per cent of the stools with a p H of 6.0 and 15.7 per cent of those with p H > 6.0 had reducing substances a n d / o r glucose. Most of the alkaline feces which contained carbohydrates were excreted by patients who were receiving antibiotics.
Of the 332 patients with diarrhea, 255 were lactose intolerant at various stages of their diarrhea (Fig. 1). Of 195 patients with mud intolerance, 39 had acid stools, and 34 excreted carbohydrates in the feces; the remaining 122 patients had stools with both of these findings. In 93.2 per cent of these 195 patients, the stools were positive in more than 10 per cent of the total samples analyzed. Of the 60 infants with severe intolerance, 58 had stools with carbohydrates and with a p H of less than 6.0. A significant number of the stools of all patients with lactose intolerance had a normal p i t and no detectable carbohydrates; multiple fresh stools had to be examined to detect such intolerance. Moreover, the period of diarrhea when each of the patients had lactose intolerance varied; 35 per cent of the 60 infants with severe in-
7 64
Li/shitz et al.
The Journal of Pediatrics November 1971
'~176 1 9,r
80
taJ
o~
70-
--
6050-
40Z tat
--
30-
20-
100
DIET
I
1T <7
~
[
IT 7-21
~
I
IT >21
DAYS OF DIARRHEA BEFORE LACTOSE ELIMINATION
Fig. 3. The correlation between duration of diarrhea and severity of lactose intolerance with response to dietary treatment. Initial treatment with a lactose-free diet (I) was followed by a disaccharide-free diet (II) if loose stools persisted. The percentage of patients who did not improve following each dietary manipulation is shown. In mild lactose intolerance ( ~ ) 12, 27, and 42 patients, and in severe lactose intolerant (Ill) 5, 17, and 23 infants, respectively, were given dietary treatment at each of the 3 time periods. The proportions of patients with diarrhea in each period were significantly different from one another in the patients with severe lactose in-
tolerance (P <0.01).
tolerance had acid stools and excreted carbohydrates in the feces during the initital stage of diarrhea, 16.6 per cent during the later period, and 48.4 per cent had no specific pattern. Of the 195 mildly lactoseintolerant patients, 36 per cent had early intolerance, 24 per cent during the later stages, and 40 per cent had no definite pattern. The severity of the lactose intolerance was correlated with the duration of the diarrhea (Fig. 2). Lactose-tolerant infants had a short course; and all but 2 of them recovered uneventfully within 3 weeks while receiving a milk formula. Of 195 infants with mild lactose intolerance, 111 had spontaneous recoveries but at a slower rate; 39 patients of this group required treatment before 3 weeks of diarrhea, and 27.5 per
cent of those 156 infants remaining on milk formula had loose stools for more than 3 weeks. Even among the 60 patients with severe intolerance, 16 had spontaneous recoveries while receiving a milk formula, but the diarrhea was the most prolonged; 22 patients of this group were treated before 3 weeks of diarrhea, and 62 per cent of those 38 infants remaining had loose stools for more than 21 days. The response of the infants to dietary therapy was dependent upon both the severity of the lactose intolerance and the duration of the diarrhea (Fig. 3). During the first week of diarrhea, 60 to 67 per cent of infants with severe or mild lactose intolerance responded to a lactose-free diet, and the remaining ones responded to a disaccharide-free diet. After 7 days' duration the severity of the lactose intolerance became a critical factor in recovery; 67 per cent of the mildly intolerant patients still responded to a lactose-free diet, in contrast to 35 per cent of infants with severe intolerance. Furthermore, 7.5 per cent with mild and 18 per cent with severe intolerance required a carbohydrate-free diet before the diarrhea ceased. An intolerance to all disaccharides and to all monosaccharides was usually present when lactose intolerance lasted for more than 3 weeks. A monosaccharide intolerance during tile acute stage of the illness was observed in 3.6 per cent of all the mildly lactose-intolerant and in 16.6 per cent of all the severely lactose-intolerant patients. In these infants the diarrhea improved only after all carbohydrates were eliminated from the diet, as previously described2 ~, 18 Seven patients developed pneumatosis intestinalis during the time they had diarrhea and lactose intolerance. 1G Lactose intolerance was positively correlated with the nutritional status of the patients (Table I ) . There was a gradual increase in the proportion of stools that contained sugars and an acid p H with increasing severity of malnutrition. Lactose intolerance could not be correlated with the history of previous episodes
Volume 79 Number 5
Carbohydrate intolerance with diarrhea
765
Table I. Correlation between nutritional status and the capacity to tolerate lactose
No. of patients 32 69 134 97
Lactose tolerance status (% of patients) Mildly Severely Tolerant intolerant intolerant
% Deficit body weight
Nutritional status
O- 9 10-24 25-40 ~40
Well-nourished Mildly malnourished Moderately malnourished Severely malnourished*
37.5 27.5 21.6 19.6
46.9 58.1 61.2 54.6
15.6 14.4 25.8 25.8
The proportions of patients of each group, according to their lactose intolerance status~ were significantly different from one another (P < 0.017). *Twenty-three had kwashiorkor.
of gastroenteritis, with the presence of enteropathogens in the stools, with the presence of parasites, or with other associated infections. Antibiotic therapy produced an increase in fecal p H but did not influence the excretion of sugars. The proportion of acid stools was 32.5 per cent in patients who did not receive antibiotics, as compared to 17.3 per cent in those who did (P < 0.05), yet the excretion of carbohydrates was similar in each group. DISCUSSION Dietary carbohydrates not absorbed by the small intestine pass into the large bowel and undergo partial hydrolysis and fermentation by bacterial action. 7 Consequently, the feces contain carbohydrates and organic acids, resulting in an acid p H of the stools as low as 4.5. 4 The determination of reducing substances a n d / o r glucose and of the p H in feces by simple semiquantitative methods can be detected and may be utilized for the diagnosis of the capacity to tolerate dietary carbohydrates. However, most fecal samples analyzed at random with these simple bedside methods have a p H of 6.0 or more and contain concentrations of carbohydrates below clinical significance. Thus in order to assess the capacity of infants with diarrhea to tolerate checked daily throughout the illness in recarbohydrates, 2 to 3 liquid stools should be lation to a specific dieta~T intake. A diagnosis of carbohydrate intolerance can be made when reducing substances and glucose are excreted in the stools in concentrations
above 0.25 per cent and 1% respectively, and/or when the p H of the stools is below 6.0. By these criteria, 77 per cent of our patients with severe diarrhea had lactose intolerance during the acute stage of the illness. The tests described must be performed immediately after excretion of the stools. The concentrations of carbohydrates, lactic acid, and fecal p H change very rapidly due to exogenous bacterial fermentation. 1~ An electronic device to signal each bowel movement is useful. 2~ Antibiotic therapy and the type of sugar in the diet must also be considered in interpreting the results of the measurements of p H and sugar in stools. The fecal p H is dependent upon the bacterial fermentation of carbohydrates, 4, ~ and any factor modifying this relationship may alter the stool p H without influencing the capacity to tolerate carbohydrates per se. Sucrose is not a reducing sugar and will not react with commercially available tapes for glucose or with tablets for reducing substances. Preliminary hydrolysis of the stool to split sucrose into glucose and fructose can be done by using 1NHC1 instead of water for dilution and boiling for 30 secondsY 1 The monosaccharities produced are reducing sugars and will react with the test materials. The carbohydrate intolerance was always transient, varying in duration from a few days to several weeks. Many of the infants who had lactose intolerance recovered spontaneously while being given a milk formula. In some, diarrhea persisted even after recovery from the intolerance to carbohydrates.
766
Lifshitz et al.
All infants tolerated lactose a n d received milk f o r m u l a again within 4 months after the d i a r r h e a improved, 22 including those who were not able to tolerate monosaccharides during the acute stages. TM 16, is I n severe d i a r r h e a l disease of infancy, several possible mechanisms might p r o d u c e a reduction in the net absorption of carbohydrates by the intestine. D u r i n g the acute stage of the illness, these patients m a y have diminished t r a n s p o r t of glucose by the intestinal mucosa, 2s i m p a i r e d absorption of carbohydrates, 2~ a n d a deficit of the enzymes necessary for the hydrolysis of dietary disaccharides? -z Clinical observations have confirmed the deleterious role of lactose in malnourished children with diarrhea. 25 These children m a y have a deficiency of intestinal disaccharidases2G, 27 a n d an i m p a i r e d absorptive c a p a c i t y to all d i e t a r y carbohydrates. 2s W h a t e v e r the m e c h a n i s m or mechanisms responsible for the diminished absorption of carbohydrates in infants with diarrhea, the consequence is prolongation of the diarrhea. A p r o m p t diagnosis of the capacity to tolerate dietary carbohydrates is essential. T h e elimination of lactose (and other specific carbohydrates) from the diet of these infants results in p r o m p t improvement, and the chronic d i a r r h e a resulting in intolerance to other disaccharides, and intolerance to all carbohydrates including monosaccharides such as fructose, 15' is m a y be prevented. Such potentially fataI complications as pneumatosis intestinalis m a y also be prevented by a p p r o p r i a t e a n d timely dietary treatment. 1~ A n outline of the dietary m a n a g e m e n t of infants with d i a r r h e a is given elsewhere. ~2 We wish to thank the nurses and house staff for their help and enthusiasm. Our thanks is extended to Dr. Marvin Cornblath for his critical review of this manuscript. REFERENCES 1. Finkelstein, H., and Meyer, L. F.: Zur technik und Indikation der Ernabrung mit Eiweissmilch, Munch. Med. Wochensehr. 58: 340, 1911.
The ]ournaI of Pediatrics November 1971
2. Howland, J.: Prolonged intolerance to carbohydrates, Trans. Am. Pediatr. Soc. 53: 11, 192I. 3. Holzel, A., Schwarz, V., and Sutcliffe, K. W.: Defective lactose absorption causing malnutrition in infancy, Lancet. 1: 1126, 1959. 4. Weijers, H. A., Van de Kamer, J. H., Dicke, W. K., and Ijsseling, J.: Diarrhea caused by deficiency of sugar splitting enzymes. I., Acta Paediatr. 50: 55, 1961. 5. Lifshitz, F., and Holman, G. H.: Disaccharidase deficiencies with steatorrhea, J. PEDIATR. 64: 34, 1964. 6. Sunshine, P., and Kretchmer, N.: Studies of small intestine during development. III. Infantile diarrhea associated with intolerance to disaccharides, Pediatrics 34: 38, 1964. 7. Haemmerli, U. P., Kistler, H., Ammann, M., Marthaler, T., Semenza, G., Auricchio, S., and Prader, A.: Acquired milk intolerance in the adult caused by lactose malabsorption due to a selective deficiency of intestinal lactase activity, Am. J. Med. 38: 7, 1965. 8. Lifshitz, F.: Congenital lactase deficiency, J. PEDIATR. 69: 229, 1966. 9. Holzel, A., Mereu, T., and Thompson, M. L.: Severe lactose intolerance in infancy, Lancet 2: 1346, 1962. 10. Weijers, H. A., and Van de Kamer, J. H.: Diarrhea caused by deficiency of sugar splitting enzymes. II., Acta Paediatr. 51: 371, 1962. i1. Auricchio, S., Dahlqvlst, A., Murset, G., and Prader, A.: Isomaltose intolerance causing decreased ability to utilize dietary starch, J. P~DI~TR. 62: 165, 1963. 12. McMichael, H. B., Webb, J., and Dawson, A. M.: Lactase deficiency in adults. A cause of "functional" diarrhoea, Lancet h 717, 1965. 13. Auricchio, S., and Rublno, A.: Intestinal glycosidase activities in congenltal malabsorption of disaccharides, J. PEDIATR. 66: 55, 1965. 14. Kerry, K. R., and Anderson, C. M.: A ward test for sugar in feces, Lancet 1: 981, 1964. 15. Lifshitz, F., Coello-Ramirez, P., and Gutierrez-Topete, G.: Monosaccharide intolerance and hypoglycemia in infants with diarrhea. I. Clinical course of 23 infants, J. PEDIATR. 77: 595, 1970. 16. Coello-Ramirez, P., Gutierrez-Topete, G., and Lifshitz, F.: Pneumatosis intestinalis, Am. J. Dis. Child. 120: 3, I970. 17. NatreIla, M. G.: Experimental statistics, National Bureau of Standards, Handbook 91, Washington, D. C., 1963. 18. Lifshitz, F., Coello-Ramirez, P., and Gutierrez-Topete, G.: Monosaccharide intolerance and hypoglycemia in infants with diarrhea. lI. Metabolic studies in 23 infants, J. PEmATR. 77: 604, 1970. 19. Lifshitz, F., Cornado-Cornet, M. C., and Coello-Ramirez, P.: Excretion of lactic acid and carbohydrates in the stools of infants with diarrhea. To be published.
Volume 79 Number 5
20. Lifshitz, F., Diaz-Bensussen, S., MartinezGarza, V., Abdo-Bassols, F., and Diaz Del Castillo, E.: The influence of disaccharides on the development of systemic acidosis in the premature infant, Pedlatr. Res. 5: 213, 1971. 21. Townley, R. R. W.: Disaccharidase deficiency in infancy and childhood, Pediatrics 38: 127, 1966. 22. Lifshitz, F., Coello-Ramirez, P., and Contreras-Gutierrez, M. L.: The response to carbohydrate oral loads of infants with diarrhea, J. PI~DIATll. 23. Torres-Pinedo, R., Rivera, C. L,, and Fernandez, S.: Studies on infant diarrhea. II. Absorption of glucose and net fluxes of water and sodium chloride in a segment of the jejunum, J. Clin. Invest. 45: 1916, 1966. 24. Rodriguez-de-Curet, It., Lugo-de-Rivera, C.,
Carbohydrate intolerance with diarrhea
25. 26. 27.
28.
76 7
and Torres-Pinedo, R.: Studies on infant diarrhea. IV. Sugar transit and absorption in small intestine after a feeding, Gastroenterology 59: 396, 1970. Dean, R. F. A.: The treatment of kwashiorkor with milk and vegetable proteins, Br. Med. J. 2: 791, 1952. Bowie, M. D., Brinckman, G. L., and Hanse, J, D. L.: Diarrhea in protein-calorie malnutrition, Lancet 2: 550, 1963. Bowie, M. D., Brinekman, G. L., and Hansen, J. D. L.: Acquired disaeeharide intolerance in maInutHtion, J. PEDIATR. 66: 1083, 1965. James, W. P. T.: Sugar absorption and intestinal motility in children when malnourished and after treatment, Clin. Sci. 39: 305, 1970.
November, I971 T h e ] o u r n a l of P E D I A T R I C S
Carbohydrate intolerance "infants ith diarrhea In infants hospitalized with severe diarrhea, lactose intolerance was considered to be present when the stools had a carbohydrate content greater than 0.25 per cent, and~or a p H of less than 6.0. By these criteria, 255 or 77 per cent of 332 infants had lactose intolerance. All but 2 of the 77 lactose-tolerant patients recovered within 3 weeks while receiving a milk formula, whereas 111 of 195 with mild intolerance ( ~ 30 per cent positive stools) and 13 of 60 with severe lactose intolerance ( ~ 30 per cent positive stoo{s) recovered while receiving a milk formula. Diarrhea lasted more than 3 weeks in 27 per cent o[ those with mild and in 62 per cent of those with untreated severe intolerance; with dietary treatment a prompt [avorable response was elicited. Lactose intolerance was positively correlated with increasing severity of malnutrition but not with previous episodes of gastroenteritis, the presence of enteropathogens, or associated infections. Antibiotic therapy increased the stool pH toward alkaline but did not modify the excretion of carbohydrates.
Fima Lifshitz, M.D.,* Pedro Coello-Ramirez, M.D., Guillermo Gutierrez-Topete, M.D., and Maria Cinta Cornado-Cornet, Q.F.B. MEXICO
C I T Y t M E X I C O ~ AND B A L T I M O R E
T~E INFLUZ~C~ OF carbohydrates on the pathogenesis of diarrhea has been studied since the early part of this century, z In 1921, Howland'-' classified infants with diarrhea into those who had congenital difFrom the Hospital de Pediatria, Centro Medico Nacional, I.M.S.S., the Department of Pediatrics, University of Maryland Hospital, and Rosewood State Hospital. Read in part before the I V Congreso de Pediatria de Ias Naciones Latinas, Guadalajara, ]al, Mexico, December 9, 1968. ~Reprlnt address: Department of Pediatrics, University of Ma'ryland Hospital, Baltimore, Md. 21201.
VoI. 79~ No. 5, pp. 760-767
AND O W I N G S
M I L L S ~ MD.
ficu!ties with ingested carbohydrates, those with a temporary alteration following gastroenteritis, and those with prolonged carbohydrate intolerance. Subsequently, it was shown that diarrhea resulted from a deficiency of the enzymes necessary for hydrolysis of dietary disaccharides and that improvement occurred only after the offending carbohydrate was eliminated from the diet? -s The evaluation of the capacity of patients with diarrhea to tolerate carbohydrates has varied from clinical observations following
Volume 79 Number 5
Carbohydrate intolerance with diarrhea
empirical dietary changes to the measurements of blood sugar levels after the oral administration of-disaceharides and their component monosaecharides?, 9 In addition, quantification of organic acids and carbohydrates in feces*, 10, n and measurements of disaccharidase activity in homogenates of intestinal mucosa ~-~, 12, 13 have been reported. These techniques, although accurate, are not applicable for general clinical use. The purpose of this report is to describe the results of the use of simple bedside methods to determine reducing substances 1. and p H in multiple fresh stool specimens of 332 infants with diarrhea. These tests were useful in detecting a reduced capacity to tolerate lactose in 77 per cent of these patients. MATERIALS
AND METHODS
From December 1, 1967, to January 30, 1969, 332 of 403 infants with severe diarrhea admitted to one of the diarrhea wards of the Hospital de Pediatria, Centro Medico Nacional, I.M.S.S., were studied during the acute stage of their illness. At the time of admission, the mean age of the patients was 5.8 _+ 1.8 months, mean body weight, 4.66 _+ 0.72 Kg., and mean length 59.8 + 2.3 cm. (_+ 95% confidence intervals). In only 32 infants was the body weight within normal limits of age and length for Mexican infants; in all others there was malnutrition of varying degrees. All 332 patients were dehydrated and had metabolic acidosis and electrolyte deficits; 191 had had previous episodes of gastroenteritis. The duration of the diarrhea prior to admission varied from 2 days to 3 months. Enteropathogens (E. coli, Shigella, Salmonella) were cultured from the stools of 126 infants, Entamoeba histolytica of 5, and Giardia lamblia of 12. Ninety patients had infections in addition to diarrhea. The patients had been fed milk prior to admission to the hospital. After admission, all were given fluids and electrolytes intravenously. Milk feedings were begun 8 to 24 hours after admission and by 36 hours, the infants were receiving 150 ml. per kilogram
76 1
of body weight per day of a full-strength milk formula containing 4.5 per cent lactose (20 cal. per 30 ml.). Milk was given throughout the course to 204 infants; a formula containing a different carbohydrate was substituted after varying intervals of diarrhea in 128 patients. The decision to initiate dietary therapy varied with the duration and severity of the illness and the presence of stools with an acid p H and carbohydrates. All 67 patients who had diarrhea for more than 3 weeks were given dietary treatment. In addition, 17 and 44 infants of the group who excreted acid stools and carbohydrates were arbitrarily selected for treatment during the first week, and between 1 and 3 weeks of diarrhea, respectively. Treatment was begun with a lactose-free diet, followed by a disaccharide-free, then a carbohydrate-free diet if the diarrhea persisted.15, a6 Antibiotics were given to 134 patients; indications for antibiotic therapy were often related to the presence of enteropathogens in the stools or other nonenteric infections. Two or 3 fresh stools per day were collected throughout the diarrheal period and immediately assayed for pH, reducing substances, and glucose. The fecal p H was determined directly from the stool water, and the concentrations of carbohydrates were measured after a 1:2 dilution? 4 Urinary contamination of the specimens was avoided by using a urine collector. Reducing substances in the feces were determined by Clinitest tablets, and glucose and p H by Combistix (Ames Co., Division Miles Labs, Elkhart, Ind.). The p H of some stool samples was simultaneously determined with a glass electrode (Beckman Expanded Scale p H Meter, Model 76, Beckman Instruments Inc., Fullerton, Calif.). The correlation coefficient between both methods for measurements of fecal p H was r = 0.94 (Y = 0.588 + 0.932x; Y --= Potentiometer, X -=- Combistix) ; the estimated variance of the slope was 0.0048 and of the intercept 0.0208. Therefore, all p H values used in the analyses were those obtained by use of Combistix. There were 3,450 liquid stool samples
762
Lifshitz et al.
P
The Journal of Pediatrics November 1971
P
P < o.ool
OOO
t)
>6.0
6,0 pH
<6.0
0.25 %
NEG
~>0 . 5 0 %
REDUCING SUBSTANCES
NEG
+
++
GLUCOSE
Fig. 1. pH, reducing substances, and glucose in diarrheal stools. The pH and carbohydrate content of stools from 77 patients who tolerated lactose ( | ) , are compared with those of 195 patients with mild lactose intolerance ( D ) , and with those of 60 patients with severe lactose intolerance (~-~). The mean number of stools excreted per day, per patient during the study period was similar for the 3 groups of patients: 5.36, 6.08, and 6.12, respectively. The mean intakes of milk formula for the 3 groups of patients were similar: 138, 137, and 143 ml. per kilogram per day, respectively.
analyzed for pH, 3,427 for reducing substances, and 3,401 for glucose, from 332 patients with diarrhea while receiving a milk formula. The mean number of stools analyzed per day, per patient was 2.31, and the mean number of stools excreted per day was 5.88. A patient with diarrhea was considered to have lactose intolerance if, while receiving a milk formula, he excreted stools with reducing substances or glucose in concentrations above 0.25 per cent and 1+, respectively, and/or with a p H of less than 6.0. The period of diarrhea during which the patients manifested lactose intolerance varied: (a) initial stage: within 72 hours after beginning milk formula, (b) later stage: after the first week of hospitalization, and (c) no specific pattern: intermittently, throughout the course of diarrhea. The severity of lactose intolerance was assessed by the proportion of liquid stools containing reducing substances and/or glucose, and with a pH of less than 6.0 while the patient received milk formula. Lactose intolerance was considered to be mild when less than 30 per cent of the stool samples were positive. The intolerance was defined
as severe when more than 30 per cent had positive tests. Lactose intolerance was considered to be specific for this disaccharide when improvement of diarrhea followed the elimination of lactose from the diet. The intolerance was considered to be generalized to all disaccharides or to all monosaccharides, when the improvement occurred after the institution of disaccharide-free or carbohydrate-free feedings, respectively. The results of the stool analyses were compared with those of (a) 213 normal stools from 20 infants who did not have diarrhea (the mean age, weight, and length were similar to those of patients with diarrhea), (b) 443 fecal samples of 114 milk fed infants following the first 3 days after recovery from diarrhea, and (c) 269 stools of 54 patients with diarrhea who were fasting. There were no significant differences in the parameters measured in these 3 groups; thus all the data were combined as control material. Statistical treatment of the data was performed by chi square tests comparing the differences between proportions on a twovariables classification. 17
Volume 79 Number 5
Carbohydrate intolerance with diarrhea
763
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DAYS OF DIARRHEA Fig, 2. Duration of diarrhea in patients receiving milk formula. The percentages of patients who persisted with loose stools at different time intervals, corrected for the number of infants who died or who were removed for dietary therapy at each interval. Of 77 lactose-tolerant patients (@ O ) , 3 died before the diarrhea ceased, and 2 were given dietary treatment after 21 days. Of 195 infants with mild lactose intolerance (x x), 3 died before recovery, and 81 were given dietary treatment. Of 60 patients with severe lactose intolerance ([-] [[]), 2 died, and 45 required dietary treatment. The proportions of patients with persistent diarrhea in each group were significantly different from one another (P ( 0 . 0 1 ) .
RESULTS
During the period of milk intake, 27.4 per cent of the liquid stools from the diarrhea group were acid, 17.4 per cent contained reducing substances, and 10.3 per cent had glucose. In contrast, 3.7 per cent of the control specimens had a p H less than 6.0, and less than 1.0 per cent of the specimens contained carbohydrates (P < 0.01). The presence of carbohydrates in the stools was positively correlated with the fecal pH. Carbohydrates were found in 57.2 per cent of the stools with p H < 6.0, whereas only 38.4 per cent of the stools with a p H of 6.0 and 15.7 per cent of those with p H > 6.0 had reducing substances a n d / o r glucose. Most of the alkaline feces which contained carbohydrates were excreted by patients who were receiving antibiotics.
Of the 332 patients with diarrhea, 255 were lactose intolerant at various stages of their diarrhea (Fig. 1). Of 195 patients with mud intolerance, 39 had acid stools, and 34 excreted carbohydrates in the feces; the remaining 122 patients had stools with both of these findings. In 93.2 per cent of these 195 patients, the stools were positive in more than 10 per cent of the total samples analyzed. Of the 60 infants with severe intolerance, 58 had stools with carbohydrates and with a p H of less than 6.0. A significant number of the stools of all patients with lactose intolerance had a normal p i t and no detectable carbohydrates; multiple fresh stools had to be examined to detect such intolerance. Moreover, the period of diarrhea when each of the patients had lactose intolerance varied; 35 per cent of the 60 infants with severe in-
7 64
Li/shitz et al.
The Journal of Pediatrics November 1971
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DAYS OF DIARRHEA BEFORE LACTOSE ELIMINATION
Fig. 3. The correlation between duration of diarrhea and severity of lactose intolerance with response to dietary treatment. Initial treatment with a lactose-free diet (I) was followed by a disaccharide-free diet (II) if loose stools persisted. The percentage of patients who did not improve following each dietary manipulation is shown. In mild lactose intolerance ( ~ ) 12, 27, and 42 patients, and in severe lactose intolerant (Ill) 5, 17, and 23 infants, respectively, were given dietary treatment at each of the 3 time periods. The proportions of patients with diarrhea in each period were significantly different from one another in the patients with severe lactose in-
tolerance (P <0.01).
tolerance had acid stools and excreted carbohydrates in the feces during the initital stage of diarrhea, 16.6 per cent during the later period, and 48.4 per cent had no specific pattern. Of the 195 mildly lactoseintolerant patients, 36 per cent had early intolerance, 24 per cent during the later stages, and 40 per cent had no definite pattern. The severity of the lactose intolerance was correlated with the duration of the diarrhea (Fig. 2). Lactose-tolerant infants had a short course; and all but 2 of them recovered uneventfully within 3 weeks while receiving a milk formula. Of 195 infants with mild lactose intolerance, 111 had spontaneous recoveries but at a slower rate; 39 patients of this group required treatment before 3 weeks of diarrhea, and 27.5 per
cent of those 156 infants remaining on milk formula had loose stools for more than 3 weeks. Even among the 60 patients with severe intolerance, 16 had spontaneous recoveries while receiving a milk formula, but the diarrhea was the most prolonged; 22 patients of this group were treated before 3 weeks of diarrhea, and 62 per cent of those 38 infants remaining had loose stools for more than 21 days. The response of the infants to dietary therapy was dependent upon both the severity of the lactose intolerance and the duration of the diarrhea (Fig. 3). During the first week of diarrhea, 60 to 67 per cent of infants with severe or mild lactose intolerance responded to a lactose-free diet, and the remaining ones responded to a disaccharide-free diet. After 7 days' duration the severity of the lactose intolerance became a critical factor in recovery; 67 per cent of the mildly intolerant patients still responded to a lactose-free diet, in contrast to 35 per cent of infants with severe intolerance. Furthermore, 7.5 per cent with mild and 18 per cent with severe intolerance required a carbohydrate-free diet before the diarrhea ceased. An intolerance to all disaccharides and to all monosaccharides was usually present when lactose intolerance lasted for more than 3 weeks. A monosaccharide intolerance during tile acute stage of the illness was observed in 3.6 per cent of all the mildly lactose-intolerant and in 16.6 per cent of all the severely lactose-intolerant patients. In these infants the diarrhea improved only after all carbohydrates were eliminated from the diet, as previously described2 ~, 18 Seven patients developed pneumatosis intestinalis during the time they had diarrhea and lactose intolerance. 1G Lactose intolerance was positively correlated with the nutritional status of the patients (Table I ) . There was a gradual increase in the proportion of stools that contained sugars and an acid p H with increasing severity of malnutrition. Lactose intolerance could not be correlated with the history of previous episodes
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Carbohydrate intolerance with diarrhea
765
Table I. Correlation between nutritional status and the capacity to tolerate lactose
No. of patients 32 69 134 97
Lactose tolerance status (% of patients) Mildly Severely Tolerant intolerant intolerant
% Deficit body weight
Nutritional status
O- 9 10-24 25-40 ~40
Well-nourished Mildly malnourished Moderately malnourished Severely malnourished*
37.5 27.5 21.6 19.6
46.9 58.1 61.2 54.6
15.6 14.4 25.8 25.8
The proportions of patients of each group, according to their lactose intolerance status~ were significantly different from one another (P < 0.017). *Twenty-three had kwashiorkor.
of gastroenteritis, with the presence of enteropathogens in the stools, with the presence of parasites, or with other associated infections. Antibiotic therapy produced an increase in fecal p H but did not influence the excretion of sugars. The proportion of acid stools was 32.5 per cent in patients who did not receive antibiotics, as compared to 17.3 per cent in those who did (P < 0.05), yet the excretion of carbohydrates was similar in each group. DISCUSSION Dietary carbohydrates not absorbed by the small intestine pass into the large bowel and undergo partial hydrolysis and fermentation by bacterial action. 7 Consequently, the feces contain carbohydrates and organic acids, resulting in an acid p H of the stools as low as 4.5. 4 The determination of reducing substances a n d / o r glucose and of the p H in feces by simple semiquantitative methods can be detected and may be utilized for the diagnosis of the capacity to tolerate dietary carbohydrates. However, most fecal samples analyzed at random with these simple bedside methods have a p H of 6.0 or more and contain concentrations of carbohydrates below clinical significance. Thus in order to assess the capacity of infants with diarrhea to tolerate checked daily throughout the illness in recarbohydrates, 2 to 3 liquid stools should be lation to a specific dieta~T intake. A diagnosis of carbohydrate intolerance can be made when reducing substances and glucose are excreted in the stools in concentrations
above 0.25 per cent and 1% respectively, and/or when the p H of the stools is below 6.0. By these criteria, 77 per cent of our patients with severe diarrhea had lactose intolerance during the acute stage of the illness. The tests described must be performed immediately after excretion of the stools. The concentrations of carbohydrates, lactic acid, and fecal p H change very rapidly due to exogenous bacterial fermentation. 1~ An electronic device to signal each bowel movement is useful. 2~ Antibiotic therapy and the type of sugar in the diet must also be considered in interpreting the results of the measurements of p H and sugar in stools. The fecal p H is dependent upon the bacterial fermentation of carbohydrates, 4, ~ and any factor modifying this relationship may alter the stool p H without influencing the capacity to tolerate carbohydrates per se. Sucrose is not a reducing sugar and will not react with commercially available tapes for glucose or with tablets for reducing substances. Preliminary hydrolysis of the stool to split sucrose into glucose and fructose can be done by using 1NHC1 instead of water for dilution and boiling for 30 secondsY 1 The monosaccharities produced are reducing sugars and will react with the test materials. The carbohydrate intolerance was always transient, varying in duration from a few days to several weeks. Many of the infants who had lactose intolerance recovered spontaneously while being given a milk formula. In some, diarrhea persisted even after recovery from the intolerance to carbohydrates.
766
Lifshitz et al.
All infants tolerated lactose a n d received milk f o r m u l a again within 4 months after the d i a r r h e a improved, 22 including those who were not able to tolerate monosaccharides during the acute stages. TM 16, is I n severe d i a r r h e a l disease of infancy, several possible mechanisms might p r o d u c e a reduction in the net absorption of carbohydrates by the intestine. D u r i n g the acute stage of the illness, these patients m a y have diminished t r a n s p o r t of glucose by the intestinal mucosa, 2s i m p a i r e d absorption of carbohydrates, 2~ a n d a deficit of the enzymes necessary for the hydrolysis of dietary disaccharides? -z Clinical observations have confirmed the deleterious role of lactose in malnourished children with diarrhea. 25 These children m a y have a deficiency of intestinal disaccharidases2G, 27 a n d an i m p a i r e d absorptive c a p a c i t y to all d i e t a r y carbohydrates. 2s W h a t e v e r the m e c h a n i s m or mechanisms responsible for the diminished absorption of carbohydrates in infants with diarrhea, the consequence is prolongation of the diarrhea. A p r o m p t diagnosis of the capacity to tolerate dietary carbohydrates is essential. T h e elimination of lactose (and other specific carbohydrates) from the diet of these infants results in p r o m p t improvement, and the chronic d i a r r h e a resulting in intolerance to other disaccharides, and intolerance to all carbohydrates including monosaccharides such as fructose, 15' is m a y be prevented. Such potentially fataI complications as pneumatosis intestinalis m a y also be prevented by a p p r o p r i a t e a n d timely dietary treatment. 1~ A n outline of the dietary m a n a g e m e n t of infants with d i a r r h e a is given elsewhere. ~2 We wish to thank the nurses and house staff for their help and enthusiasm. Our thanks is extended to Dr. Marvin Cornblath for his critical review of this manuscript. REFERENCES 1. Finkelstein, H., and Meyer, L. F.: Zur technik und Indikation der Ernabrung mit Eiweissmilch, Munch. Med. Wochensehr. 58: 340, 1911.
The ]ournaI of Pediatrics November 1971
2. Howland, J.: Prolonged intolerance to carbohydrates, Trans. Am. Pediatr. Soc. 53: 11, 192I. 3. Holzel, A., Schwarz, V., and Sutcliffe, K. W.: Defective lactose absorption causing malnutrition in infancy, Lancet. 1: 1126, 1959. 4. Weijers, H. A., Van de Kamer, J. H., Dicke, W. K., and Ijsseling, J.: Diarrhea caused by deficiency of sugar splitting enzymes. I., Acta Paediatr. 50: 55, 1961. 5. Lifshitz, F., and Holman, G. H.: Disaccharidase deficiencies with steatorrhea, J. PEDIATR. 64: 34, 1964. 6. Sunshine, P., and Kretchmer, N.: Studies of small intestine during development. III. Infantile diarrhea associated with intolerance to disaccharides, Pediatrics 34: 38, 1964. 7. Haemmerli, U. P., Kistler, H., Ammann, M., Marthaler, T., Semenza, G., Auricchio, S., and Prader, A.: Acquired milk intolerance in the adult caused by lactose malabsorption due to a selective deficiency of intestinal lactase activity, Am. J. Med. 38: 7, 1965. 8. Lifshitz, F.: Congenital lactase deficiency, J. PEDIATR. 69: 229, 1966. 9. Holzel, A., Mereu, T., and Thompson, M. L.: Severe lactose intolerance in infancy, Lancet 2: 1346, 1962. 10. Weijers, H. A., and Van de Kamer, J. H.: Diarrhea caused by deficiency of sugar splitting enzymes. II., Acta Paediatr. 51: 371, 1962. i1. Auricchio, S., Dahlqvlst, A., Murset, G., and Prader, A.: Isomaltose intolerance causing decreased ability to utilize dietary starch, J. P~DI~TR. 62: 165, 1963. 12. McMichael, H. B., Webb, J., and Dawson, A. M.: Lactase deficiency in adults. A cause of "functional" diarrhoea, Lancet h 717, 1965. 13. Auricchio, S., and Rublno, A.: Intestinal glycosidase activities in congenltal malabsorption of disaccharides, J. PEDIATR. 66: 55, 1965. 14. Kerry, K. R., and Anderson, C. M.: A ward test for sugar in feces, Lancet 1: 981, 1964. 15. Lifshitz, F., Coello-Ramirez, P., and Gutierrez-Topete, G.: Monosaccharide intolerance and hypoglycemia in infants with diarrhea. I. Clinical course of 23 infants, J. PEDIATR. 77: 595, 1970. 16. Coello-Ramirez, P., Gutierrez-Topete, G., and Lifshitz, F.: Pneumatosis intestinalis, Am. J. Dis. Child. 120: 3, I970. 17. NatreIla, M. G.: Experimental statistics, National Bureau of Standards, Handbook 91, Washington, D. C., 1963. 18. Lifshitz, F., Coello-Ramirez, P., and Gutierrez-Topete, G.: Monosaccharide intolerance and hypoglycemia in infants with diarrhea. lI. Metabolic studies in 23 infants, J. PEmATR. 77: 604, 1970. 19. Lifshitz, F., Cornado-Cornet, M. C., and Coello-Ramirez, P.: Excretion of lactic acid and carbohydrates in the stools of infants with diarrhea. To be published.
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20. Lifshitz, F., Diaz-Bensussen, S., MartinezGarza, V., Abdo-Bassols, F., and Diaz Del Castillo, E.: The influence of disaccharides on the development of systemic acidosis in the premature infant, Pedlatr. Res. 5: 213, 1971. 21. Townley, R. R. W.: Disaccharidase deficiency in infancy and childhood, Pediatrics 38: 127, 1966. 22. Lifshitz, F., Coello-Ramirez, P., and Contreras-Gutierrez, M. L.: The response to carbohydrate oral loads of infants with diarrhea, J. PI~DIATll. 23. Torres-Pinedo, R., Rivera, C. L,, and Fernandez, S.: Studies on infant diarrhea. II. Absorption of glucose and net fluxes of water and sodium chloride in a segment of the jejunum, J. Clin. Invest. 45: 1916, 1966. 24. Rodriguez-de-Curet, It., Lugo-de-Rivera, C.,
Carbohydrate intolerance with diarrhea
25. 26. 27.
28.
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and Torres-Pinedo, R.: Studies on infant diarrhea. IV. Sugar transit and absorption in small intestine after a feeding, Gastroenterology 59: 396, 1970. Dean, R. F. A.: The treatment of kwashiorkor with milk and vegetable proteins, Br. Med. J. 2: 791, 1952. Bowie, M. D., Brinckman, G. L., and Hanse, J, D. L.: Diarrhea in protein-calorie malnutrition, Lancet 2: 550, 1963. Bowie, M. D., Brinekman, G. L., and Hansen, J. D. L.: Acquired disaeeharide intolerance in maInutHtion, J. PEDIATR. 66: 1083, 1965. James, W. P. T.: Sugar absorption and intestinal motility in children when malnourished and after treatment, Clin. Sci. 39: 305, 1970.