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Monosaccharide intolerance and hypoglycemia in infants with diarrbea. I. Clinical course of 23 infants
October, 1970 T h e J o u r n a l of P E D I A T R I C S
595
Monosaccbaride intolerance and hypoglycemia in infants ruth diarrhea. L Clinical course of 23 infants Twenty-three patients had monosaccharide intolerance after an episode of gastroenteritis. The feces were liquid, acid, and contained carbohydrates as long as the diet provided sugar of any sort. When carbohydrates were eliminated from the diet, the diarrhea improved. However, hypoglycemia complicated the clinical courses of 17 patients when they were fed carbohydrate-free diets, and it was considered to be the cause of death in 3 of these infants. The malabsorption of monosaecharides was transient, varying in duration from a few days to several weeks. These patients were also unable to tolerate disaccharides during the time that they had monosaccharide intolerance. The ability to tolerate monosaccharides was often correlated with the presence of bacteria in the duodenal fluid. After antibiotic therapy, some of these infants recovered the capacity to tolerate carbohydrates.
Fima Lifshitz, M.D., Pedro Coello-Ramirez, M.D., and Guillermo Guti~rrez-Topete, M.D., with the technical assistance of Miguel Le6n Contreras Guti~rrez MEXIGO
CITY,
MEXICO
C H R O N I C D I A R R H E A, clinically indistinguishable from that caused .by intestinal disaccharidase deficiencies, may also be caused by monosaccharide malabsorption. Two groups of such patients have been distinguished: those with a primary, familial,
From the Hospital de PediatHa, Gentro Mddico Nacional, I.M.S.S. Read in part before the Lawson Wilkins Memorial Reunion, The Johns Hopkins Hospital, Baltimore, Md., April 28, 1969. Reprint address: Fima Lilshitz, Department of Pediatrics, The University o[ Maryland Ir Baltimore, Md. 21201.
autosomal recessive disorder, thought to be due to a defective, glucose-specific carrier mechanism, 1-14 and those with a secondary, nonspecific, temporary monosaccharide intolerance? T M Hypoglycemia has not been reported hitherto in any of them. We describe here our findings in 23 patients with diarrhea and intolerance to all dietary carbohydrates, including monosaccharides such as fructose. All had courses similar to those of infants described by Burke and Danks? 6 In 17 of them, hypoglycemia was shown to play an important role in the clinical course and final outcome. In a second Vol. 77, No. 4, pp. 595-603
596
Li[shitz, Coello-Ramlrez, and Gutidrrez-Topete
paper we describe the metabolic studies carried out to help elucidate the possible mechanisms involved in producing hypoglycemia in children with monosaccharide intolerance. 18 MATERIAL
AND METHODS
Of 403 infants with diarrhea investigated at the Hospital de Pediatrla, Centro M6dico Nacional, I.M.S.S., 23 had persistent diarrhea and intolerance to carbohydrates; these 23 patients were the subjects of the study. Fourteen of them were boys, and at the time of admission, their ages ranged from 11 days to 10 months. Only 2 infants had normal body weights, 18 had varying degrees of marasmus, and 3 had kwashiorkor. Ten patients had had repeated episodes of gastroenteritis throughout life, and all 23 had diarrhea and were severely dehydrated, with metabolic acidosis and marked electrolyte deficits. The duration of the diarrhea prior to admission varied from 4 days to 3 months. The general approach to the infant with diarrhea, as well as the clinical characteristics of the total population of patients, is thoroughly described elsewhere. 19 T h e patients were fed milk during the episode of diarrhea that preceded their admission to the hospital. Afterward, in addition to milk formula, 3 other diets were used; each was constituted with the same basal mixture but a different carbohydrate. The "carbohydrate-free" diet contained calcium caseinate, corn oil, mineral salts, and water to provide amounts of protein, fat, and electrolyte approximately equal to those ordinarily obtained from milk. When glucose was added, it was called "glucose diet," and when it contained sucrose it was named "lactose-free diet." The concentration of these carbohydrates varied from 2.5 to 10 per cent. The diet employed was determined by the clinical course and by the tolerance shown by each infant. At the time of admission to the hospital, the patients were given a milk formula; subsequently this was replaced by a lactose=free a n d / o r glucose diet. Since the diarrhea persisted, the infants were then given a carbohydrate-free diet.
The Journal o[ Pediatrics October 1970
Eight patients developed pneumatosis intestinalis 2~ and were fasted from the time the diagnosis was made until the radiolucent images in the wall of the intestine disappeared; they were then given a carbohydratefree diet. Three of them had pneumatosis intestinalis at the time of admission; the other 5 developed this complication 2 to 11 days later, while they were being fed a milk formula. 21 When the diarrhea improved, the different carbohydrates were reintroduced into the diet of all the patients, starting with glucose, followed by sucrose, and finally by lactose. These changes were usually made after the specific oral load of sugar was tolerated. The capacity to tolerate carbohydrates was determined by the changes in character of the stools that were induced by the carbohydrate in the diet while the patient had diarrhea and by the response to sugar loads during the diarrhea-free periods, as described elsewhere.21.22 Intolerance was judged to be present when diarrhea was induced by the dietary carbohydrate or by the oral load of sugar, when the pH of the stool decreased to less than 6.0, and when the stool contained more than 0.25 per cent reducing substances a n d / o r more than 1+ of glucose. The patients' blood sugar concentrations were carefully followed with Dextrostix (Ames Co., Inc., Elkhart, Ind.) a n d / o r determinations of reducing sugars 2a from the time of diagnosis of glucose intolerance and duriiag the carbohydrate tolerance tests. An infant was considered to have hypoglycemia when the blood glucose and reducing sugar levels were less than 40 mg. per cent. A reduced absorption of a carbohydrate after an oral load was considered to exist when reducing sugars in the serum were elevated less than 40 rag. per cent above their fasting levels. A curve was considered flat when less than a 20 mg. per cent rise occurred. The presence of ketosis and ketonuria was determined by Acetest tablets while the patients were receiving a carbohydrate-free diet. At the time of admission to the hospital, 3 stools were collected serially from each patient for routine cultures and for investiga-
Volume 77 Number 4
Monosaccharide intolerance and hypoglycemia
tion for parasites. Subsequently these analyses were repeated at the time of diagnosis of monosaccharide intolerance, and a single sample of duodenal fluid was obtained. Intubation of the duodenum was carried out with a polyethylene tube after a 4 hour fast; the position of the tube in the duodenum was 5 to 10 cm. from the stomach. The nasopharynx was washed with sodium bicarbonate solution. The first aspirated sample was employed for investigation for parasites; the second was immediately cultured. Duodenal cultures were repeated after antibiotic therapy. The data were analyzed statistically according to Natrella. 24 RESULTS
All 23 patients had similar courses of diarrhea. T h e patients who received milk had lactose intolerance during the acute stage of their illnesses; the stools continued to be liquid, had acid pH's, and contained carbohydrates, even though milk had been replaced by a lactose-free diet a n d / o r a glucose diet. As soon as all carbohydrates were eliminated from the diet, the diarrhea improved. However, studies directed toward the absorption of fat and protein were not carried out. Hypoglycemia complicated the clinical courses of 17 infants when they were fed carbohydrate-free diets. Only one of them had ketosis and ketonuria before developing low blood sugar levels. This group of patients was given glucose continuously, intravenously, when fed a carbohydrate-free diet to prevent a n d / o r to treat hypoglycemia. D u r i n g this time 2 of them had acute episodes of hypoglycemia despite receiving intravenous fluids containing 3.3 per cent glucose. As soon as the patients tolerated a diet with small concentrations of glucose after a diarrhea-free period, they started maintaining a normal blood sugar level between formula feedings. However, when this concentration of carbohydrate induced diarrhea again, hypoglycemia persisted. The blood sugar levels remained above 4:0 rag. per cent only when a 10 per cent glucose intake was given, but the
597
diarrhea and intolerance worsened. Actually, the needs of glucose in the diet had to be titrated against the amount that was sufficient to maintain normal blood sugar concentration for the time elapsed between formula feedings. The monosaccharide malabsorption was transient, varying in duration from a few days to several weeks. Fourteen infants recovered the capacity to tolerate small amounts of glucose in the diet at different periods of time after the diarrhea improved. Two of these patients had recurrence of diarrhea and glucose intolerance on the twenty-eighth and thirty-second days, respectively, after improvement following 8 and 10 days of the dietary intake of 10 per cent glucose. T h e remaining 9 patients who had monosaccharide intolerance and hypoglycemia died before recovering the capacity to tolerate glucose. Five of them died within 3 to 19 days after the diarrhea improved, while they were still receiving a carbohydratefree diet. T h e other 4. infants were given a 2.5 per cent glucose diet after being free of diarrhea for 3 to 18 days; it was not tolerated and they developed diarrhea again that persisted until their deaths. Hypoglycemia was considered to be the cause of death of 3 patients; one of them died after an acute episode, while he was receiving intravenous fluids containing 3.3 per cent glucose. The other 2 infants developed hypoglycemic crises within 3 hours after the intravenous infusion of fluids infiltrated the subcutaneous tissues. These 3 infants had convulsions and deteriorated during the time they were being fed a carbohydrate-free diet and after 5 to 10 days of having had no diarrhea. Five other patients developed severe infections which did not respond to antibiotic therapy; one infant had a massive hemorrhage of undetermined origin. Clinical improvement of diarrhea associated with the institution of the carbohydratefree diet was not immediately associated with better handling of oral carbohydrate loads. In 91 of the infants, a diminished capacity to tolerate monosaccharides was documented. During the first 15 days free of
59 8
Li[shitz, Coello-Ramlrez, and Gutidrrez-Topete
The Journal o[ Pediatrics October 1970
+60
F SERUM REDUCING
+40
SUGARS
(rag / I 0 0
roll +20
BASAL
I
1
!
30 MINUTES
I
I
60 AFTER
ORAL
I
90 LOAD
Fig. 1. The response to oral loads of monosaccharides is shown as the induced rise in serum reducing sugars over the fasting levels. Twenty-one patients were given 38 tolerance tests during the first 15 days free of diarrhea ( 0 - - 0 ) . Seven of them were tested with glucose, galactose, and fructose, 2 with glucose and fructose, 1 with glucose and galactose, 10 with glucose only, and 1 with fructose only. From the sixteenth to the fifty-second days after improvement, 9 infants were given 12 oral loads (• x). Four of them were tested with glucose, 1 with galactose, 4 with fructose, and 3 with a glucose-galactose combination. After the sixtieth day free of diarrhea, 6 patients received one tolerance test each ( O - - O ) . Three of them were tested with glucose, 2 with a glucose-galactose combination, and 1 with fructose. Although the metabolic handling of these carbohydrates is different, the mean rise in serum reducing sugars over the fasting levels was similar with the different monosaecharides employed during the initial period after the diarrhea improved. In the subsequent periods there were too few tolerance tests of each of the carbohydrates to try to establish such differences. The differences in the mean level of serum reducing sugars attained during the first 30 minutes after the oral load as recovery of the patients progressed were highly significant. (Data are means +-95 per cent confidence intervals.)
diarrhea, 19 of them developed loose stools with acid p H ' s and containing carbohydrates, after being given an oral load of glucose, galactose, a n d / o r fructose. I n the remaining 2 patients, diarrhea was not induced by the oral load of glucose, although they had flat curves; however, when they received fructose they had evidence of marked intolerance. T h e difference in response to these oral loads of monosaccharides as recovery of the patients progressed is shown in Fig. 1. Initially, all infants had flat or reduced curves with m a x i m u m elevation of the serum concentration of reducing sugars occurring 90 minutes after the oral load and producing marked intolerance. Gradually the absorption of carbohydrates improved: After the fifteenth day free of diarrhea, the patients had elevations of the serum levels of reducing sugar of 40
mg. per cent or more above the fasting levels, regardless of persistent delayed absorption and intolerance; after the sixtieth day they h a d ' a normal response. T h e patients were also unable to tolerate any disaccharide during the time that they had monosaccharide intolerance. Nine of them were given a total of 16 disaccharide tolerance tests during the first 2 months in which they were free of diarrhea. After the oral load of maltose, sucrose, a n d / o r lactose, they had flat tolerance curves, diarrhea was induced, the p H of the stools fell, a n d they excreted carbohydrates. I n contrast, the 7 patients who were studied with 11 tolerance tests after they had recovered the capacity to tolerate monosaccharides also tolerated t h e oral load of the 3 disaccharides tested. At this time they had reduced or normal tol-
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Monosaccharide intolerance and hypoglycemia
erance curves with a mean increment in serum concentration of reducing sugars of 37 mg. per cent above the fasting levels, and no stool changes were detectable. The capacity to tolerate monosaccharides correlated with the presence of bacteria in the intestine, as described in 1966 by Burke and Anderson is in neonates with sugar intolerance following surgery of the gastrointestinal tract. Infected duodenal fluid was found in 18 of the patients during the acute stage of illness (Table I ) . After antibiotic therapy the duodenal cultures of 13 patients became negative; coincidentally, 12 of them recovered the ability to tolerate monosaccharides. One of them required three 8 day courses of antibiotics before Salmonella paratyphi B was eliminated from the duodenum; only then was glucose tolerated. 21 One of the 2 patients who developed a recurrence of diarrhea and glucose intolerance again had in the duodenal fluid and feces the same bacteria that had been found during the acute stage. The other infant had a simultaneous growth of 2 organisms; both were different from the one found initially. These 2 patients were re-treated with antibiotics and improved when glucose was again eliminated from the diet; this carbohydrate was later tolerated when the duodenal cultures became negative in the first infant and showed less growth in the second (Klebsiella sp. persisted). The patient who did not tolerate glucose in the diet after his duodenal fluid became sterile was an infant who had Salmonella typhi murium during the acute stage of the illness; after 5 days of antibiotic therapy and during the third day of normal stools, the duodenum was sterile. However, a 2.5 per cent glucose diet again induced diarrhea. Subsequently he developed staphylococcal pneumonia which caused his death. No repea t cultures of the duodenal fluid were performed after antibiotic therapy in 2 infants; they died before recovering the capacity to tolerate glucose. In one of them a different organism from the one found in the duodenal fluid and stools during the acute stage was cultured from small intestinal ulceration at the time of postmortem
5 99
examination. Three patients continued to have positive duodenal cultures after antibiotic therapy (Table I ) ; throughout this time they continued to have diarrhea alternating with periods of normal stools for up to 18 days whenever they were fed a carbohydrate-free diet, and they developed diarrhea and intolerance to glucose when this carbohydrate was given in the diet in a 2.5 per cent concentration. They failed to thrive and had hypoglycemia despite feedings at 2 hour intervals. Subsequently they died before recovering the capacity to tolerate glucose. The 2 infants who had sterile duodenal fluid during the acute stage of the illness received antibiotics for 8 to 10 days before the cultures were obtained. In the interim they had glucose intolerance, and after a carbohydrate-free diet was given the diarrhea improved. Subsequently, one infant died without recovering the capacity to tolerate glucose; the same pathogens that were found in the stools during the acute stage were cultured from intestinal ulcerations in the small and large bowels at the time of a postmortem examination. The other patient recovered uneventfully. The duodenal fluid was not studied in 3 patients during the time that they had monosaccharide intolerance. However, 2 of them had pathogens cultured from intestinal ulcerations on postmortem examinations; these organisms were different from those found in the stools during the acute stage (Table I ) . DISCUSSION The patients described here were considered to have monosaccharide intolerance during the acute stage of their illness because they had diarrhea with acid stools containing carbohydrate while they ingested sugar and because they improved promptly when all carbohydrates were eliminated from the diet. I n addition, intolerance to oral loads of monosaccharide was proved in 21 of them during the first 15 days free of diarrhea. The malabsorption was transient and the duration varied from a few days to several weeks. The possibility that alterations of the small
600
Li/shitz, Coello-Ramlrez,
and Gutigrrez-Topete
The Journal o/ Pediatrics October 1970
T a b l e I. C l i n i c a l e v o l u t i o n a n d b a c t e r i a l f l o r a of p a t i e n t s w i t h m o n o s a c c h a r i d e intolerance Patient
Clinical evolution
.
Cultures Duodenal fluid ]
Stools
1
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Salm. derby Salm. para B
Salm. derby Salm. para B
2
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- E. coli 0126
E. coli 0126
3
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- E. coli, nonpath.
Salm. derby E. coli 0111
4
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Klebs. sp.
Klebs. sp.
5
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Klebs. sp.
Klebs. sp.
6
Improved (can tolerate carbohydrates)
Klebs. sp.
E. coli 0119
7
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp.
Klebs. sp.
8
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp. Staph. aureus E. eoli, nonpath.
Proteus mr. + vI. Klebs. sp. Paracolon sp.
9
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp.
Proteus mr. Klebs. sp.
10
Hypoglycemia; improved (can tolerate carbohydrates)
E. coli 0111 Staph. aureus Giardia lamblia
E. coli 0111
I1
Pneumatosis intestinalis; hypoglycemia; recurrence of glu- Klebs. sp. cose intolerance and duodenal fluid showed Klebs. sp.; improved (can tolerate carbohydrates)
1Klebs. sp.
12
Pneumatosis intestinalis; hypoglycemia; recurrence of glu- E. coli 0 i l l cose intolerance and duodenal fluid showed Klebs. sp.; and Klebs. sp.; improved (can tolerate carbohydrates)
E. coli 0 I l l E. coli 0126
13
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp. Paracolon sp.
14
Hypoglycemia; improved (can tolerate carbohydrates)
E. eoli 0119
15
Hypoglycemia; died of sepsis before tolerating carbohy- - drates; autopsy cultures from intestinal ulcerations showed Salm. B
E. coli, nonpath. Klebs. sp. Proteus mr.
16
Hypoglycemia; died of hypoglycemia before tolerating car- - bohydrates; autopsy cultures from intestinal ulcerations showed Salm. G
SaIm. derby
17
Pneumatosis intestinalis; hypoglycemia; died of pneumonia E. coli, nonpath. before tolerating carbohydrates
E. coli, nonpath.
18
Hypoglycemia; died of hypoglycemia before tolerating car- Klebs. sp. bohydrates; autopsy cultures from intestinal ulcerations showed E. coli 0126
Klebs. sp. Proteus vl. E. coli, nonpath.
19
Hypoglycemia; died of hypoglycemia before tolerating car- Neg. bohydrates; autopsy cultures from intestinal ulcerations showed E. eoli 011f and Salm. paratyphi B
E. eoli 0111 Salm. para B
Neg.
The depicted cultures are those obtained during the acute stage of the illness, at the time of diagnosis of monosaccharide intolerance. After antibiotic therapy, the cultures of the duodenal fluid became negative in the first 12 patients and in patient No. 20. No repeat cultures were performed on patients No. 17 and 18. The last 3 infants continued to have bacterial growth from the duodenal fluid throughout their hospital course.
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Monosaccharide intolerance and hypoglycemia
60 1
Table I. Cont'd Cultures Patient ] Clinical evolution Duodenal fluid I Stools 20 Hypoglycemia; died of pneumonia before tolerating carbo- Salm. typhimu Salm. typhimu hydrates; diarrhea and intolerance after diarrhea-free period, until death 21
Hypoglycemia; died of pneumonia before tolerating carbo- Klebs. sp. hydrates; diarrhea and intolerance after diarrhea-free Staph. aureus period, until death~after antibiotics cultures of duodenal fluid showed Klebs. and micrococcus sp.
E. coli 0124 Salm. derby
22
Hypoglycemia; died of hemorrhage before tolerating carbo- E. coli, nonpath. hydrates; diarrhea and intolerance after diarrhea-free Klebs: sp. period, until death~after antibiotics cultures of duodenal fluid showed Klebs. and Proteus sp.
E. cog 0126
23
Hypoglycemia; died of pneumonia before tolerating carbo- E. coli 0126 hydrates; diarrhea and intolerance after diarrhea-free period, until death--after antibiotics cultures of duodenal fluid showed Klebs. sp.
E. coli 0126
bowel flora could cause such an upset in the dynamics of small intestinal absorption should be considered in this group of infants. In a variety of diseases involving the intestine, malabsorption has been attributed to the proliferation of bacteria in the small bowel, and therapy directed against the organism has reversed the malabsorption. 25-29 A similar mechanism may be responsible for monosaccharide malabsorption in our patients and in those described by Burke and Anderson? 5 However, there is as yet no precise knowledge of how bacteria could disturb sugar digestion and transport mechanisms at a step in the absorption that is shared by the 3 monosaccharides tested. T h e specificity of this alteration also remains to be elucidated. Interestingly the bacteria isolaiced from the duodenal fluid during the acute stage of the illnesses of 12 of the patients were organisms rarely considered to be enteropathogenicY ~ Presently we are collecting data regarding the incidence of positive duodenal cultures in infants from a comparable population admitted to the hospital without diarrheal disease or with diarrhea and milder types of carbohydrate intolerance. I n patients with pneumatosis intestinalis who were able to tolerate monosaecharides, a sterile duodenal fluid has been found. 21
Whatever the mechanism or mechanisms responsible for the diminished absorption of monosaccharides in these patients, the consequence is development of diarrhea and carbohydrate intolerance that characteristically disappears when the unabsorbed sugar is eliminated from the diet. When a carbohydrate is not absorbed by the intestine, it passes into the large bowel and undergoes partial hydrolysis and fermentation by bacterial actionY 1 Consequently the feces contain carbohydrates and organic acids, specifically lactic acid, and the p H of the stools may fall as low as 4.5. 32 An osmotic effect is exerted in the intestine by the intact carbohydrates and by some products of bacterial degradation? a Some of these appear to have, in addition, a direct irritating effect on the intestinal mucosa that stimulates intestinal motility, leading to diarrhea. Thus the primary mechanisms of diarrhea in patients with monosaccharide intolerance might be analogous to that of osmotic diuresis in the renal tubule. Failure of absorption of a specific solute from the intestinal lumen would result in reduced absorption of water as well as other solutes, even if the concentration of the specific unabsorbed carbohydrates were well below 300 mOsm. per liter (for example, less than 5 per cent glucose). In support of
60 2
Lifshitz, Coello-RarMrez, and Gutidrrez-Topete
this view, feeding the infants a formula with a reduced concentration of glucose in the diet produced a m a r k e d diarrhea with carbohydrate in the stool. It should be recalled that 1 per cent glucose in glomerular filtrate produces a gross osmotic dinresis in normal kidneys. I n diarrheal disease of infancy there is impaired absorption of glucose? 4 However, most patients tolerate a diet containing carbohydrate twice isotonic in strength. W e have studied 403 patients with severe diarrhea; only the 23 infants described here did not improve until all carbohydrates were eliminated from t h e diet. I n contrast, 56 patients were unable to tolerate any disaccharide and were successfully treated with a diet containing 10 per cent glucose? 9 After the diarrhea improved, the patients with monosaccharide intolerance did not tolerate the specific oral load with the 20 per cent carbohydrate solution, whereas the patients with diarrhea who had a normal capacity to tolerate a fullstrength glucose diet were also able to tolerate the oral load of the same monosaccharide solution during the first week free of diarrhea .i9 T h e ability of young infants to tolerate carbohydrate-free diets was first reported by von Chwalibogowski s5 in 1937. Such a diet has proved useful in the treatment of patients with the primary familial disorder of glucosegalactose malabsorption" and in patients with secondary acquired monosaccharide intolerance such as the ones reported here? s-aT I t is reasonable to expect that m a n y more cases of diarrhea and intolerance to all carbohydrates will be identified and treated in the future. Since a carbohydrate-free diet is now commercially available (Borden Co., New York, N. Y.), it is most important to keep in mind a complication of its use, namely hypoglycemia. Attention was called to low blood sugar levels complicating the treatment of patients with intolerance to monosaccharides by Harries and Franc is~; however, they did not d o c u m e n t this particular finding. Since severe hypoglycemia is by no means always symptomatic, its clinical significance m a y not be recognized, as seen in the patient
The Journal of Pediatrics October 1970
described by A b r a h a m and associates, 11 with the primary type of glucose-galactose realabsorption. T h e mechanism producing hypoglycemia in patients with monosaccharide intolerance is a complicated one, as described elsewhere? s
REFERENCES
1. Lindquist, B., and Meeuwisse, G. W.: Chronic diarrhoea caused by monosaecharide malabsorption, Acta Paediat. Stand. 51: 674, 1962. 2. Lindqulst, B., Meeuwisse, G. W., and Melin, K.: Glucose-galactose malabsorption, Lancet 2: 666, 1962. 3. Lindquist, B., and Meeuwisse, G. W.: Intestinal transport of monosaccharldes in generalized and selective malabsorption, Acta Paediat. Scan& (Suppl.) 146" i10, 1963. 4. Lindquist, B., Meeuwlsse, G. W., and Melln, K.: Osmotic diarrhoea in genetically transmitted glucose-galactose malabsorption, Acta Paediat. Scand. 52" 217, 1963. 5. Laplane, R., Plonovsky, C., Etienne, M., Debray, P., Lods, J. C., and Pissarro, B.: L'intol~rance aux sucres a transfert intestinal aetif. Ses rapports avee l'intol~rance an lactose et le syndrome coeliaque, Arch. Franc. Pediat. 19,' 895, 1962. 6. Anderson, C. M., Kerry, K. R., and Townley, R. R. W.: An inborn defect of intestinal absorption of certain monosaccharides, Arch. Dis. Child. 40: 1, 1965. 7. Linneweh, F., Schauml6ffel, E., and Bartelmai, W.: Angeborene Glucose-und Galaktose Malabsorption, Klin. Wsehr. 43" 409, 1965. 8. Marks, J. F., Norton, J. B., and Fordtran, J. S.: Glucose-galactose malabsorption, J. P~DIAT. 69" 22, 1966. 9. Schneider, A. J., Kinter, W. B., and Stirling, C. E.: Glucose-galactose malabsorptlon. Report of a case with autoradlographic studies 'of a mucosal biopsy, New Eng. J. Med. 274: 305, 1966. 10. Eggermont, E., and Loeb, H.: Giueose-galactose intolerance, Lancet 2" 343, 1966. 11. Abraham, J. M., Lenin, B., Oberholzer, V. G., and Russell, A.: Glucose-galaetose malabsorption, Arch. Dis. Child. 42" 592, 1967. 12. Gray, M. G.: Malabsorption of carbohydrate, Fed. Proc. 26" 1415, 1967. 13. Meeuwisse, G. W., and Dahlqvist, A.: Glucose-galaetose malabsorption. A study with biopsy of the small intestinal mueosa, Acta Paediat. Scan& 57. 273, 1968. 14. Meeuwisse, G. W., and Melin, K.: Studies in gIucose-galactose malabsorption, Acta Paedlat. Scan& (Suppl.) 188: 1, 1969. 15. Burke, V,, and Anderson, C. M.: Sugar intoIerance as a cause of protracted diarrhoea following surgery of the gastrointestinal tract in neonates, Aust. Paediat. J. 2: 219, 1966. 16. Burke, V., and Danks, D. M.: Monosaecha-
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22. 23. 24. 25. 26.
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Monosaccharide intolerance and hypoglycemia
ride malabsorption in young infants, Lancet 1: 1177, 1966. Harries, J. T., and Francis, D. E. M.: Temporary monosaccharide intolerance, Acta Paediat. Scand. 57: 505, 1968. Lifshitz, F., Coello-Ramlrez, P., and Guti~rrez-Topete, G.: Monosaceharide intolerance and hypoglycemia in infants with diarrhea. II. Metabolic studies in 23 infants, J. PEDIAT. 77: 604, 1970. Lifshitz, F., Coello-Ramlrez, P., and Gutigrrez-Topete, G.: Carbohydrate intolerance in infants with diarrhea. To be published. Mackenzie, E. P.: Pneumatosis intestinalis. Review of the literature with report of 13 cases, Pediatrics 7- 537, 1951. Coello-Ramirez, P., Guti~rrez-Topete, G., Lifshitz, F., and Diaz-Bensussen, S.: Pneumatosis intestinalis, Amer. J. Dis. Child. In press. Kerry, K. R., and Anderson, C. M.: A ward test for sugar in feces, Lancet 1: 981, 1964. Nelson, N.: Photometric adaptation of the Somogyi method for the determination of glucose, J. Biol. Chem. 153: 375, 1944. Natrella, M. G.: Experimental statistics, National Bureau of Standards, Handbook 91, Washington, D. C., 1963. Badenoch, J.: Steatorrhea in the adult, Brit. Med. J. 2: 963, 1960. Doig, A., and Girwood, R. H.: Absorption of folic acid and labelled cyanocobalamin in intestinal malabsorption: With observations on faecal excretion of fat and nitrogen absorption of glucose and xylose, Quart. J. Med. 53(N.S. 29): 333, 1960. Wirts, C. W., and Goldstein, F.: Studies of
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mechanism of post-gastrectomy steatorrhea, Ann. Intern. Med. 58: 25, 1963. Paulk, E. A., Jr., and Farrar, W. E., Jr.: Diverticulosis of small intestine and megaloblastic anemia. Intestinal mieroflora and absorption before and after tetracycline administration, Amer. J. Med. 37: 473, 1964. Salem, G., Goldstein, F., and Wirts, G. W.: Malabsorption in intestinal scleroderma: Relation to bacterial flora and treatment with antibiotics, Ann. Intern. Med. 64: 834, 1966. Weil, A. J., Subash Ramchand, M. B., and Arias, M. E.: Nosocomial infection with Klebsiella type 25, New Eng. J. Med. 275: 17, 1966. Haemmerli, U. P., Kistter, H., Ammann, R., Marthaler, T., Semenza, G., Auriechio, S., and Prader, A.: Acquired milk intolerance in the adult caused by lactose malabsorption due to a selective deficiency of intestinal lactase activity, Amer. J. Med. 38" 7, 1965. Weijers, H. A., Van de Kamer, J. H., Dicke, W. K., and Ijsseling, J.: Diarrhoea caused by deficiency of sugar splitting enzymes. I, Acta Paediat. 50: 55, 1961. Launiala, K.: The mechanism of diarrhoea in congenital disaecharide malabsorption, Acta Paediat. Scand. 57: 425, 1968. Torres-Pinedo, R., Rivera, C. L., and Ferns 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. von Chwalibogowski, A.: Experimentaluntersuchungen fiber Kaloriseh Ausreichende, Qualitativ Einseitige Ernghrung des S~iuglings, Acta Paediat. 22: 110, 1937.
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Monosaccbaride intolerance and hypoglycemia in infants ruth diarrhea. L Clinical course of 23 infants Twenty-three patients had monosaccharide intolerance after an episode of gastroenteritis. The feces were liquid, acid, and contained carbohydrates as long as the diet provided sugar of any sort. When carbohydrates were eliminated from the diet, the diarrhea improved. However, hypoglycemia complicated the clinical courses of 17 patients when they were fed carbohydrate-free diets, and it was considered to be the cause of death in 3 of these infants. The malabsorption of monosaecharides was transient, varying in duration from a few days to several weeks. These patients were also unable to tolerate disaccharides during the time that they had monosaccharide intolerance. The ability to tolerate monosaccharides was often correlated with the presence of bacteria in the duodenal fluid. After antibiotic therapy, some of these infants recovered the capacity to tolerate carbohydrates.
Fima Lifshitz, M.D., Pedro Coello-Ramirez, M.D., and Guillermo Guti~rrez-Topete, M.D., with the technical assistance of Miguel Le6n Contreras Guti~rrez MEXIGO
CITY,
MEXICO
C H R O N I C D I A R R H E A, clinically indistinguishable from that caused .by intestinal disaccharidase deficiencies, may also be caused by monosaccharide malabsorption. Two groups of such patients have been distinguished: those with a primary, familial,
From the Hospital de PediatHa, Gentro Mddico Nacional, I.M.S.S. Read in part before the Lawson Wilkins Memorial Reunion, The Johns Hopkins Hospital, Baltimore, Md., April 28, 1969. Reprint address: Fima Lilshitz, Department of Pediatrics, The University o[ Maryland Ir Baltimore, Md. 21201.
autosomal recessive disorder, thought to be due to a defective, glucose-specific carrier mechanism, 1-14 and those with a secondary, nonspecific, temporary monosaccharide intolerance? T M Hypoglycemia has not been reported hitherto in any of them. We describe here our findings in 23 patients with diarrhea and intolerance to all dietary carbohydrates, including monosaccharides such as fructose. All had courses similar to those of infants described by Burke and Danks? 6 In 17 of them, hypoglycemia was shown to play an important role in the clinical course and final outcome. In a second Vol. 77, No. 4, pp. 595-603
596
Li[shitz, Coello-Ramlrez, and Gutidrrez-Topete
paper we describe the metabolic studies carried out to help elucidate the possible mechanisms involved in producing hypoglycemia in children with monosaccharide intolerance. 18 MATERIAL
AND METHODS
Of 403 infants with diarrhea investigated at the Hospital de Pediatrla, Centro M6dico Nacional, I.M.S.S., 23 had persistent diarrhea and intolerance to carbohydrates; these 23 patients were the subjects of the study. Fourteen of them were boys, and at the time of admission, their ages ranged from 11 days to 10 months. Only 2 infants had normal body weights, 18 had varying degrees of marasmus, and 3 had kwashiorkor. Ten patients had had repeated episodes of gastroenteritis throughout life, and all 23 had diarrhea and were severely dehydrated, with metabolic acidosis and marked electrolyte deficits. The duration of the diarrhea prior to admission varied from 4 days to 3 months. The general approach to the infant with diarrhea, as well as the clinical characteristics of the total population of patients, is thoroughly described elsewhere. 19 T h e patients were fed milk during the episode of diarrhea that preceded their admission to the hospital. Afterward, in addition to milk formula, 3 other diets were used; each was constituted with the same basal mixture but a different carbohydrate. The "carbohydrate-free" diet contained calcium caseinate, corn oil, mineral salts, and water to provide amounts of protein, fat, and electrolyte approximately equal to those ordinarily obtained from milk. When glucose was added, it was called "glucose diet," and when it contained sucrose it was named "lactose-free diet." The concentration of these carbohydrates varied from 2.5 to 10 per cent. The diet employed was determined by the clinical course and by the tolerance shown by each infant. At the time of admission to the hospital, the patients were given a milk formula; subsequently this was replaced by a lactose=free a n d / o r glucose diet. Since the diarrhea persisted, the infants were then given a carbohydrate-free diet.
The Journal o[ Pediatrics October 1970
Eight patients developed pneumatosis intestinalis 2~ and were fasted from the time the diagnosis was made until the radiolucent images in the wall of the intestine disappeared; they were then given a carbohydratefree diet. Three of them had pneumatosis intestinalis at the time of admission; the other 5 developed this complication 2 to 11 days later, while they were being fed a milk formula. 21 When the diarrhea improved, the different carbohydrates were reintroduced into the diet of all the patients, starting with glucose, followed by sucrose, and finally by lactose. These changes were usually made after the specific oral load of sugar was tolerated. The capacity to tolerate carbohydrates was determined by the changes in character of the stools that were induced by the carbohydrate in the diet while the patient had diarrhea and by the response to sugar loads during the diarrhea-free periods, as described elsewhere.21.22 Intolerance was judged to be present when diarrhea was induced by the dietary carbohydrate or by the oral load of sugar, when the pH of the stool decreased to less than 6.0, and when the stool contained more than 0.25 per cent reducing substances a n d / o r more than 1+ of glucose. The patients' blood sugar concentrations were carefully followed with Dextrostix (Ames Co., Inc., Elkhart, Ind.) a n d / o r determinations of reducing sugars 2a from the time of diagnosis of glucose intolerance and duriiag the carbohydrate tolerance tests. An infant was considered to have hypoglycemia when the blood glucose and reducing sugar levels were less than 40 mg. per cent. A reduced absorption of a carbohydrate after an oral load was considered to exist when reducing sugars in the serum were elevated less than 40 rag. per cent above their fasting levels. A curve was considered flat when less than a 20 mg. per cent rise occurred. The presence of ketosis and ketonuria was determined by Acetest tablets while the patients were receiving a carbohydrate-free diet. At the time of admission to the hospital, 3 stools were collected serially from each patient for routine cultures and for investiga-
Volume 77 Number 4
Monosaccharide intolerance and hypoglycemia
tion for parasites. Subsequently these analyses were repeated at the time of diagnosis of monosaccharide intolerance, and a single sample of duodenal fluid was obtained. Intubation of the duodenum was carried out with a polyethylene tube after a 4 hour fast; the position of the tube in the duodenum was 5 to 10 cm. from the stomach. The nasopharynx was washed with sodium bicarbonate solution. The first aspirated sample was employed for investigation for parasites; the second was immediately cultured. Duodenal cultures were repeated after antibiotic therapy. The data were analyzed statistically according to Natrella. 24 RESULTS
All 23 patients had similar courses of diarrhea. T h e patients who received milk had lactose intolerance during the acute stage of their illnesses; the stools continued to be liquid, had acid pH's, and contained carbohydrates, even though milk had been replaced by a lactose-free diet a n d / o r a glucose diet. As soon as all carbohydrates were eliminated from the diet, the diarrhea improved. However, studies directed toward the absorption of fat and protein were not carried out. Hypoglycemia complicated the clinical courses of 17 infants when they were fed carbohydrate-free diets. Only one of them had ketosis and ketonuria before developing low blood sugar levels. This group of patients was given glucose continuously, intravenously, when fed a carbohydrate-free diet to prevent a n d / o r to treat hypoglycemia. D u r i n g this time 2 of them had acute episodes of hypoglycemia despite receiving intravenous fluids containing 3.3 per cent glucose. As soon as the patients tolerated a diet with small concentrations of glucose after a diarrhea-free period, they started maintaining a normal blood sugar level between formula feedings. However, when this concentration of carbohydrate induced diarrhea again, hypoglycemia persisted. The blood sugar levels remained above 4:0 rag. per cent only when a 10 per cent glucose intake was given, but the
597
diarrhea and intolerance worsened. Actually, the needs of glucose in the diet had to be titrated against the amount that was sufficient to maintain normal blood sugar concentration for the time elapsed between formula feedings. The monosaccharide malabsorption was transient, varying in duration from a few days to several weeks. Fourteen infants recovered the capacity to tolerate small amounts of glucose in the diet at different periods of time after the diarrhea improved. Two of these patients had recurrence of diarrhea and glucose intolerance on the twenty-eighth and thirty-second days, respectively, after improvement following 8 and 10 days of the dietary intake of 10 per cent glucose. T h e remaining 9 patients who had monosaccharide intolerance and hypoglycemia died before recovering the capacity to tolerate glucose. Five of them died within 3 to 19 days after the diarrhea improved, while they were still receiving a carbohydratefree diet. T h e other 4. infants were given a 2.5 per cent glucose diet after being free of diarrhea for 3 to 18 days; it was not tolerated and they developed diarrhea again that persisted until their deaths. Hypoglycemia was considered to be the cause of death of 3 patients; one of them died after an acute episode, while he was receiving intravenous fluids containing 3.3 per cent glucose. The other 2 infants developed hypoglycemic crises within 3 hours after the intravenous infusion of fluids infiltrated the subcutaneous tissues. These 3 infants had convulsions and deteriorated during the time they were being fed a carbohydrate-free diet and after 5 to 10 days of having had no diarrhea. Five other patients developed severe infections which did not respond to antibiotic therapy; one infant had a massive hemorrhage of undetermined origin. Clinical improvement of diarrhea associated with the institution of the carbohydratefree diet was not immediately associated with better handling of oral carbohydrate loads. In 91 of the infants, a diminished capacity to tolerate monosaccharides was documented. During the first 15 days free of
59 8
Li[shitz, Coello-Ramlrez, and Gutidrrez-Topete
The Journal o[ Pediatrics October 1970
+60
F SERUM REDUCING
+40
SUGARS
(rag / I 0 0
roll +20
BASAL
I
1
!
30 MINUTES
I
I
60 AFTER
ORAL
I
90 LOAD
Fig. 1. The response to oral loads of monosaccharides is shown as the induced rise in serum reducing sugars over the fasting levels. Twenty-one patients were given 38 tolerance tests during the first 15 days free of diarrhea ( 0 - - 0 ) . Seven of them were tested with glucose, galactose, and fructose, 2 with glucose and fructose, 1 with glucose and galactose, 10 with glucose only, and 1 with fructose only. From the sixteenth to the fifty-second days after improvement, 9 infants were given 12 oral loads (• x). Four of them were tested with glucose, 1 with galactose, 4 with fructose, and 3 with a glucose-galactose combination. After the sixtieth day free of diarrhea, 6 patients received one tolerance test each ( O - - O ) . Three of them were tested with glucose, 2 with a glucose-galactose combination, and 1 with fructose. Although the metabolic handling of these carbohydrates is different, the mean rise in serum reducing sugars over the fasting levels was similar with the different monosaecharides employed during the initial period after the diarrhea improved. In the subsequent periods there were too few tolerance tests of each of the carbohydrates to try to establish such differences. The differences in the mean level of serum reducing sugars attained during the first 30 minutes after the oral load as recovery of the patients progressed were highly significant. (Data are means +-95 per cent confidence intervals.)
diarrhea, 19 of them developed loose stools with acid p H ' s and containing carbohydrates, after being given an oral load of glucose, galactose, a n d / o r fructose. I n the remaining 2 patients, diarrhea was not induced by the oral load of glucose, although they had flat curves; however, when they received fructose they had evidence of marked intolerance. T h e difference in response to these oral loads of monosaccharides as recovery of the patients progressed is shown in Fig. 1. Initially, all infants had flat or reduced curves with m a x i m u m elevation of the serum concentration of reducing sugars occurring 90 minutes after the oral load and producing marked intolerance. Gradually the absorption of carbohydrates improved: After the fifteenth day free of diarrhea, the patients had elevations of the serum levels of reducing sugar of 40
mg. per cent or more above the fasting levels, regardless of persistent delayed absorption and intolerance; after the sixtieth day they h a d ' a normal response. T h e patients were also unable to tolerate any disaccharide during the time that they had monosaccharide intolerance. Nine of them were given a total of 16 disaccharide tolerance tests during the first 2 months in which they were free of diarrhea. After the oral load of maltose, sucrose, a n d / o r lactose, they had flat tolerance curves, diarrhea was induced, the p H of the stools fell, a n d they excreted carbohydrates. I n contrast, the 7 patients who were studied with 11 tolerance tests after they had recovered the capacity to tolerate monosaccharides also tolerated t h e oral load of the 3 disaccharides tested. At this time they had reduced or normal tol-
Volume 77 Number 4
Monosaccharide intolerance and hypoglycemia
erance curves with a mean increment in serum concentration of reducing sugars of 37 mg. per cent above the fasting levels, and no stool changes were detectable. The capacity to tolerate monosaccharides correlated with the presence of bacteria in the intestine, as described in 1966 by Burke and Anderson is in neonates with sugar intolerance following surgery of the gastrointestinal tract. Infected duodenal fluid was found in 18 of the patients during the acute stage of illness (Table I ) . After antibiotic therapy the duodenal cultures of 13 patients became negative; coincidentally, 12 of them recovered the ability to tolerate monosaccharides. One of them required three 8 day courses of antibiotics before Salmonella paratyphi B was eliminated from the duodenum; only then was glucose tolerated. 21 One of the 2 patients who developed a recurrence of diarrhea and glucose intolerance again had in the duodenal fluid and feces the same bacteria that had been found during the acute stage. The other infant had a simultaneous growth of 2 organisms; both were different from the one found initially. These 2 patients were re-treated with antibiotics and improved when glucose was again eliminated from the diet; this carbohydrate was later tolerated when the duodenal cultures became negative in the first infant and showed less growth in the second (Klebsiella sp. persisted). The patient who did not tolerate glucose in the diet after his duodenal fluid became sterile was an infant who had Salmonella typhi murium during the acute stage of the illness; after 5 days of antibiotic therapy and during the third day of normal stools, the duodenum was sterile. However, a 2.5 per cent glucose diet again induced diarrhea. Subsequently he developed staphylococcal pneumonia which caused his death. No repea t cultures of the duodenal fluid were performed after antibiotic therapy in 2 infants; they died before recovering the capacity to tolerate glucose. In one of them a different organism from the one found in the duodenal fluid and stools during the acute stage was cultured from small intestinal ulceration at the time of postmortem
5 99
examination. Three patients continued to have positive duodenal cultures after antibiotic therapy (Table I ) ; throughout this time they continued to have diarrhea alternating with periods of normal stools for up to 18 days whenever they were fed a carbohydrate-free diet, and they developed diarrhea and intolerance to glucose when this carbohydrate was given in the diet in a 2.5 per cent concentration. They failed to thrive and had hypoglycemia despite feedings at 2 hour intervals. Subsequently they died before recovering the capacity to tolerate glucose. The 2 infants who had sterile duodenal fluid during the acute stage of the illness received antibiotics for 8 to 10 days before the cultures were obtained. In the interim they had glucose intolerance, and after a carbohydrate-free diet was given the diarrhea improved. Subsequently, one infant died without recovering the capacity to tolerate glucose; the same pathogens that were found in the stools during the acute stage were cultured from intestinal ulcerations in the small and large bowels at the time of a postmortem examination. The other patient recovered uneventfully. The duodenal fluid was not studied in 3 patients during the time that they had monosaccharide intolerance. However, 2 of them had pathogens cultured from intestinal ulcerations on postmortem examinations; these organisms were different from those found in the stools during the acute stage (Table I ) . DISCUSSION The patients described here were considered to have monosaccharide intolerance during the acute stage of their illness because they had diarrhea with acid stools containing carbohydrate while they ingested sugar and because they improved promptly when all carbohydrates were eliminated from the diet. I n addition, intolerance to oral loads of monosaccharide was proved in 21 of them during the first 15 days free of diarrhea. The malabsorption was transient and the duration varied from a few days to several weeks. The possibility that alterations of the small
600
Li/shitz, Coello-Ramlrez,
and Gutigrrez-Topete
The Journal o/ Pediatrics October 1970
T a b l e I. C l i n i c a l e v o l u t i o n a n d b a c t e r i a l f l o r a of p a t i e n t s w i t h m o n o s a c c h a r i d e intolerance Patient
Clinical evolution
.
Cultures Duodenal fluid ]
Stools
1
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Salm. derby Salm. para B
Salm. derby Salm. para B
2
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- E. coli 0126
E. coli 0126
3
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- E. coli, nonpath.
Salm. derby E. coli 0111
4
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Klebs. sp.
Klebs. sp.
5
Pneumatosis intestinalis; improved drates)
(can tolerate carbohy- Klebs. sp.
Klebs. sp.
6
Improved (can tolerate carbohydrates)
Klebs. sp.
E. coli 0119
7
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp.
Klebs. sp.
8
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp. Staph. aureus E. eoli, nonpath.
Proteus mr. + vI. Klebs. sp. Paracolon sp.
9
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp.
Proteus mr. Klebs. sp.
10
Hypoglycemia; improved (can tolerate carbohydrates)
E. coli 0111 Staph. aureus Giardia lamblia
E. coli 0111
I1
Pneumatosis intestinalis; hypoglycemia; recurrence of glu- Klebs. sp. cose intolerance and duodenal fluid showed Klebs. sp.; improved (can tolerate carbohydrates)
1Klebs. sp.
12
Pneumatosis intestinalis; hypoglycemia; recurrence of glu- E. coli 0 i l l cose intolerance and duodenal fluid showed Klebs. sp.; and Klebs. sp.; improved (can tolerate carbohydrates)
E. coli 0 I l l E. coli 0126
13
Hypoglycemia; improved (can tolerate carbohydrates)
Klebs. sp. Paracolon sp.
14
Hypoglycemia; improved (can tolerate carbohydrates)
E. eoli 0119
15
Hypoglycemia; died of sepsis before tolerating carbohy- - drates; autopsy cultures from intestinal ulcerations showed Salm. B
E. coli, nonpath. Klebs. sp. Proteus mr.
16
Hypoglycemia; died of hypoglycemia before tolerating car- - bohydrates; autopsy cultures from intestinal ulcerations showed Salm. G
SaIm. derby
17
Pneumatosis intestinalis; hypoglycemia; died of pneumonia E. coli, nonpath. before tolerating carbohydrates
E. coli, nonpath.
18
Hypoglycemia; died of hypoglycemia before tolerating car- Klebs. sp. bohydrates; autopsy cultures from intestinal ulcerations showed E. coli 0126
Klebs. sp. Proteus vl. E. coli, nonpath.
19
Hypoglycemia; died of hypoglycemia before tolerating car- Neg. bohydrates; autopsy cultures from intestinal ulcerations showed E. eoli 011f and Salm. paratyphi B
E. eoli 0111 Salm. para B
Neg.
The depicted cultures are those obtained during the acute stage of the illness, at the time of diagnosis of monosaccharide intolerance. After antibiotic therapy, the cultures of the duodenal fluid became negative in the first 12 patients and in patient No. 20. No repeat cultures were performed on patients No. 17 and 18. The last 3 infants continued to have bacterial growth from the duodenal fluid throughout their hospital course.
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Monosaccharide intolerance and hypoglycemia
60 1
Table I. Cont'd Cultures Patient ] Clinical evolution Duodenal fluid I Stools 20 Hypoglycemia; died of pneumonia before tolerating carbo- Salm. typhimu Salm. typhimu hydrates; diarrhea and intolerance after diarrhea-free period, until death 21
Hypoglycemia; died of pneumonia before tolerating carbo- Klebs. sp. hydrates; diarrhea and intolerance after diarrhea-free Staph. aureus period, until death~after antibiotics cultures of duodenal fluid showed Klebs. and micrococcus sp.
E. coli 0124 Salm. derby
22
Hypoglycemia; died of hemorrhage before tolerating carbo- E. coli, nonpath. hydrates; diarrhea and intolerance after diarrhea-free Klebs: sp. period, until death~after antibiotics cultures of duodenal fluid showed Klebs. and Proteus sp.
E. cog 0126
23
Hypoglycemia; died of pneumonia before tolerating carbo- E. coli 0126 hydrates; diarrhea and intolerance after diarrhea-free period, until death--after antibiotics cultures of duodenal fluid showed Klebs. sp.
E. coli 0126
bowel flora could cause such an upset in the dynamics of small intestinal absorption should be considered in this group of infants. In a variety of diseases involving the intestine, malabsorption has been attributed to the proliferation of bacteria in the small bowel, and therapy directed against the organism has reversed the malabsorption. 25-29 A similar mechanism may be responsible for monosaccharide malabsorption in our patients and in those described by Burke and Anderson? 5 However, there is as yet no precise knowledge of how bacteria could disturb sugar digestion and transport mechanisms at a step in the absorption that is shared by the 3 monosaccharides tested. T h e specificity of this alteration also remains to be elucidated. Interestingly the bacteria isolaiced from the duodenal fluid during the acute stage of the illnesses of 12 of the patients were organisms rarely considered to be enteropathogenicY ~ Presently we are collecting data regarding the incidence of positive duodenal cultures in infants from a comparable population admitted to the hospital without diarrheal disease or with diarrhea and milder types of carbohydrate intolerance. I n patients with pneumatosis intestinalis who were able to tolerate monosaecharides, a sterile duodenal fluid has been found. 21
Whatever the mechanism or mechanisms responsible for the diminished absorption of monosaccharides in these patients, the consequence is development of diarrhea and carbohydrate intolerance that characteristically disappears when the unabsorbed sugar is eliminated from the diet. When a carbohydrate is not absorbed by the intestine, it passes into the large bowel and undergoes partial hydrolysis and fermentation by bacterial actionY 1 Consequently the feces contain carbohydrates and organic acids, specifically lactic acid, and the p H of the stools may fall as low as 4.5. 32 An osmotic effect is exerted in the intestine by the intact carbohydrates and by some products of bacterial degradation? a Some of these appear to have, in addition, a direct irritating effect on the intestinal mucosa that stimulates intestinal motility, leading to diarrhea. Thus the primary mechanisms of diarrhea in patients with monosaccharide intolerance might be analogous to that of osmotic diuresis in the renal tubule. Failure of absorption of a specific solute from the intestinal lumen would result in reduced absorption of water as well as other solutes, even if the concentration of the specific unabsorbed carbohydrates were well below 300 mOsm. per liter (for example, less than 5 per cent glucose). In support of
60 2
Lifshitz, Coello-RarMrez, and Gutidrrez-Topete
this view, feeding the infants a formula with a reduced concentration of glucose in the diet produced a m a r k e d diarrhea with carbohydrate in the stool. It should be recalled that 1 per cent glucose in glomerular filtrate produces a gross osmotic dinresis in normal kidneys. I n diarrheal disease of infancy there is impaired absorption of glucose? 4 However, most patients tolerate a diet containing carbohydrate twice isotonic in strength. W e have studied 403 patients with severe diarrhea; only the 23 infants described here did not improve until all carbohydrates were eliminated from t h e diet. I n contrast, 56 patients were unable to tolerate any disaccharide and were successfully treated with a diet containing 10 per cent glucose? 9 After the diarrhea improved, the patients with monosaccharide intolerance did not tolerate the specific oral load with the 20 per cent carbohydrate solution, whereas the patients with diarrhea who had a normal capacity to tolerate a fullstrength glucose diet were also able to tolerate the oral load of the same monosaccharide solution during the first week free of diarrhea .i9 T h e ability of young infants to tolerate carbohydrate-free diets was first reported by von Chwalibogowski s5 in 1937. Such a diet has proved useful in the treatment of patients with the primary familial disorder of glucosegalactose malabsorption" and in patients with secondary acquired monosaccharide intolerance such as the ones reported here? s-aT I t is reasonable to expect that m a n y more cases of diarrhea and intolerance to all carbohydrates will be identified and treated in the future. Since a carbohydrate-free diet is now commercially available (Borden Co., New York, N. Y.), it is most important to keep in mind a complication of its use, namely hypoglycemia. Attention was called to low blood sugar levels complicating the treatment of patients with intolerance to monosaccharides by Harries and Franc is~; however, they did not d o c u m e n t this particular finding. Since severe hypoglycemia is by no means always symptomatic, its clinical significance m a y not be recognized, as seen in the patient
The Journal of Pediatrics October 1970
described by A b r a h a m and associates, 11 with the primary type of glucose-galactose realabsorption. T h e mechanism producing hypoglycemia in patients with monosaccharide intolerance is a complicated one, as described elsewhere? s
REFERENCES
1. Lindquist, B., and Meeuwisse, G. W.: Chronic diarrhoea caused by monosaecharide malabsorption, Acta Paediat. Stand. 51: 674, 1962. 2. Lindqulst, B., Meeuwisse, G. W., and Melin, K.: Glucose-galactose malabsorption, Lancet 2: 666, 1962. 3. Lindquist, B., and Meeuwisse, G. W.: Intestinal transport of monosaccharldes in generalized and selective malabsorption, Acta Paediat. Scan& (Suppl.) 146" i10, 1963. 4. Lindquist, B., Meeuwlsse, G. W., and Melln, K.: Osmotic diarrhoea in genetically transmitted glucose-galactose malabsorption, Acta Paediat. Scand. 52" 217, 1963. 5. Laplane, R., Plonovsky, C., Etienne, M., Debray, P., Lods, J. C., and Pissarro, B.: L'intol~rance aux sucres a transfert intestinal aetif. Ses rapports avee l'intol~rance an lactose et le syndrome coeliaque, Arch. Franc. Pediat. 19,' 895, 1962. 6. Anderson, C. M., Kerry, K. R., and Townley, R. R. W.: An inborn defect of intestinal absorption of certain monosaccharides, Arch. Dis. Child. 40: 1, 1965. 7. Linneweh, F., Schauml6ffel, E., and Bartelmai, W.: Angeborene Glucose-und Galaktose Malabsorption, Klin. Wsehr. 43" 409, 1965. 8. Marks, J. F., Norton, J. B., and Fordtran, J. S.: Glucose-galactose malabsorption, J. P~DIAT. 69" 22, 1966. 9. Schneider, A. J., Kinter, W. B., and Stirling, C. E.: Glucose-galactose malabsorptlon. Report of a case with autoradlographic studies 'of a mucosal biopsy, New Eng. J. Med. 274: 305, 1966. 10. Eggermont, E., and Loeb, H.: Giueose-galactose intolerance, Lancet 2" 343, 1966. 11. Abraham, J. M., Lenin, B., Oberholzer, V. G., and Russell, A.: Glucose-galaetose malabsorption, Arch. Dis. Child. 42" 592, 1967. 12. Gray, M. G.: Malabsorption of carbohydrate, Fed. Proc. 26" 1415, 1967. 13. Meeuwisse, G. W., and Dahlqvist, A.: Glucose-galaetose malabsorption. A study with biopsy of the small intestinal mueosa, Acta Paediat. Scan& 57. 273, 1968. 14. Meeuwisse, G. W., and Melin, K.: Studies in gIucose-galactose malabsorption, Acta Paedlat. Scan& (Suppl.) 188: 1, 1969. 15. Burke, V,, and Anderson, C. M.: Sugar intoIerance as a cause of protracted diarrhoea following surgery of the gastrointestinal tract in neonates, Aust. Paediat. J. 2: 219, 1966. 16. Burke, V., and Danks, D. M.: Monosaecha-
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ride malabsorption in young infants, Lancet 1: 1177, 1966. Harries, J. T., and Francis, D. E. M.: Temporary monosaccharide intolerance, Acta Paediat. Scand. 57: 505, 1968. Lifshitz, F., Coello-Ramlrez, P., and Guti~rrez-Topete, G.: Monosaceharide intolerance and hypoglycemia in infants with diarrhea. II. Metabolic studies in 23 infants, J. PEDIAT. 77: 604, 1970. Lifshitz, F., Coello-Ramlrez, P., and Gutigrrez-Topete, G.: Carbohydrate intolerance in infants with diarrhea. To be published. Mackenzie, E. P.: Pneumatosis intestinalis. Review of the literature with report of 13 cases, Pediatrics 7- 537, 1951. Coello-Ramirez, P., Guti~rrez-Topete, G., Lifshitz, F., and Diaz-Bensussen, S.: Pneumatosis intestinalis, Amer. J. Dis. Child. In press. Kerry, K. R., and Anderson, C. M.: A ward test for sugar in feces, Lancet 1: 981, 1964. Nelson, N.: Photometric adaptation of the Somogyi method for the determination of glucose, J. Biol. Chem. 153: 375, 1944. Natrella, M. G.: Experimental statistics, National Bureau of Standards, Handbook 91, Washington, D. C., 1963. Badenoch, J.: Steatorrhea in the adult, Brit. Med. J. 2: 963, 1960. Doig, A., and Girwood, R. H.: Absorption of folic acid and labelled cyanocobalamin in intestinal malabsorption: With observations on faecal excretion of fat and nitrogen absorption of glucose and xylose, Quart. J. Med. 53(N.S. 29): 333, 1960. Wirts, C. W., and Goldstein, F.: Studies of
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mechanism of post-gastrectomy steatorrhea, Ann. Intern. Med. 58: 25, 1963. Paulk, E. A., Jr., and Farrar, W. E., Jr.: Diverticulosis of small intestine and megaloblastic anemia. Intestinal mieroflora and absorption before and after tetracycline administration, Amer. J. Med. 37: 473, 1964. Salem, G., Goldstein, F., and Wirts, G. W.: Malabsorption in intestinal scleroderma: Relation to bacterial flora and treatment with antibiotics, Ann. Intern. Med. 64: 834, 1966. Weil, A. J., Subash Ramchand, M. B., and Arias, M. E.: Nosocomial infection with Klebsiella type 25, New Eng. J. Med. 275: 17, 1966. Haemmerli, U. P., Kistter, H., Ammann, R., Marthaler, T., Semenza, G., Auriechio, S., and Prader, A.: Acquired milk intolerance in the adult caused by lactose malabsorption due to a selective deficiency of intestinal lactase activity, Amer. J. Med. 38" 7, 1965. Weijers, H. A., Van de Kamer, J. H., Dicke, W. K., and Ijsseling, J.: Diarrhoea caused by deficiency of sugar splitting enzymes. I, Acta Paediat. 50: 55, 1961. Launiala, K.: The mechanism of diarrhoea in congenital disaecharide malabsorption, Acta Paediat. Scand. 57: 425, 1968. Torres-Pinedo, R., Rivera, C. L., and Ferns 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. von Chwalibogowski, A.: Experimentaluntersuchungen fiber Kaloriseh Ausreichende, Qualitativ Einseitige Ernghrung des S~iuglings, Acta Paediat. 22: 110, 1937.