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Disaccharide Intolerance
Disaccharide Intolerance MURRAY DAVIDSON, M.D.
Some pediatricians are confused that intense interest has developed during the last decade in clinical syndromes associated with maHunctions in digestion and assimilation of sugars. To them these supposedly new conditions represent variations of an old entity, starch intolerance. This review would be incomplete if these relationships were not clarified at the outset. The concept of starch intolerance can be traced to misinterpretations of the meaning of the observation by Herter46 that the first cases of celiac disease seen in this country appeared to be made worse upon ingestion of certain starchy foods and to reports by European workers that infants with diarrhea sometimes did not tolerate carbohydrates well.41 In his presidential address to the American Pediatric Society in 1921, John Howland50 summarized the deleterious role of carbohydrates in infants with diarrhea. He recognized that the amount of sugar ingested could make a difference in symptomatology and anticipated current speculations that this dose phenomenon is related to osmotic activity of undigested sugar particles. He classified infants who had difficulties with ingested carbohydrates into those congenitally affected, those with a temporary defect following diarrhea, and others with a prolonged course of chronic diarrhea. Unfortunately, despite Howland's almost prophetic allusion to the role of disaccharides in the problem, most of his discourse was concerned with starch intolerance. Herter's observation about the deleterious effect of some starchy foods made so vivid an impression that Howland and a number of. equally careful later workers all displayed utter disregard for the fact that Herter4 6 had indicated that the .problem occurred only with some starchy foods, but that other starchy foods were well tolerated. From the Bronx-Lebanon Hospital Center and Bronx Municipal Hospital Center, Albert Einstein College of Medicine, Bronx, New York. Preparation of this review and of any original observations referred to herein was made possible in part by support of Public Health Service Grants A~3432 from the National Institute of Arthritis and Metabolic Disease, and HD-02032 from the National Institute of Child Health and Human Development.
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It was not until the classic observations of Dicke, Weijers and Van de Kamer33 , 80 with regard to gluten, and subsequent demonstrations that gluten-induced enteropathy is associated with specific mucosallesions,3,69,79 that the correct meaning of Herter's brilliant clinical report became clear. Herter46 had not suggested that starch itself played a role, but carefully referred only to starchy foods. Nevertheless, in the 40 years between his report and that of the Dutch workers,33, 80 pediatricians focused their attentions on starch. Andersen2 reported that levels of amylase were below normal in children with "starch intolerance." In classifications of the celiac syndrome which shel proposed and which were agreed to by others,44 impairment of starch digestion was regarded as the precursor to fat intolerance. Microscopic examinations of stools for extracellular starch granules, introduced during an earlier period of descriptive pediatrics,21, 73 became the standard "scientific" test by which many children with persistent loose stools were labeled as intolerant to starch. This presumed disease was assumed to lead to malabsorption of fat if patients with starch granules in their stools were not kept on fat-free diets. In 1958 we demonstrated that microscopic examination for starch in the stool has no significance, and that diagnosis of "starch intolerance" certainly cannot be made this way.30 More recently we have indicated our conviction that children with the clinical picture usually referred to as starch intolerance are not suffering from such a condition, if indeed the entity exists at all.31 Nevertheless "mild starch intolerance" and "mild gluten intolerance" continue to be included in various classifications of malabsorptive syndromes.34 ,35 As a result, many children are unnecessarily treated with the high protein, low fat, low starch diets commonly prescribed for "starch intolerance."l, 44 In a number of instances, failure to respond results in additional restrictions of gluten-containing foods, despite failure to demonstrate the characteristic lesion of gluten-induced enteropathy. Our purpose in beginning the current discussion with a recount of the nebulous entity of "starch intolerance" is only partIy to establish the historical relations between a possible disorder of polysaccharide digestion and those of monosaccharides and disaccharides. A more important function would be ful:6.llment of our hope that dietary manipulations will be made only in patients in whom they are indicated. It would be a crushing blow if, as a result of something we wrote, children who had been treated with needless restrictions would suffer additional privation because of unindicated withdrawals of milk or simple sugars from their diets.
Physiology
It is useful to review briefly the physiology of carbohydrate assimilation before discussing the diseases associated with defects in digestion and absorption of simple carbohydrates. Salivary and pancreatic amylase digestion of starch and glycogen results in splitting of more than 90 per
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cent of these substrates to maltose (1-4 alpha-linked di-glucose) and the remainder into isomaltose (1-6 alpha -linked di-glucose ), which comes from the branching points of chains in the polysaccharide structures. Maltose, isomaltose and two disaccharides which occur naturally, sucrose (cane sugar, 1-2 alpha-linked glucose-fructose) and lactose (milk sugar, 1-4 beta-linked galactose-glucose), together with other rare disaccharides, are absorbed intact into the mucosal layer of the small intestine, where they are hydrolyzed by specific disaccharidases into their component monosaccharides. Dahlqvist, who pioneered in the separation of the disaccharidases of the intestinal mucosa, characterized them first in hog mucosa22 • 23 and then in human beings from surgical specimens. 24 He separated the enzymes by selective heat inactivation; others added gel filtration chromatography.7. 71. 72 As a result of these different methods of separation and characterization, the group in Sweden24 and the group in Zurich7 • 72 have arrived at slightly different classifications for the enzymes. It has been suggested that some of these presumed differences may be artifactual results of the separation techniques. 55 The main elements, however, of both classifications are not dissimilar. Each group agrees that two maltases are specific only for maltose and that a third maltase hydrolyzes isomaltose as well. According to the Swiss, two additional maltases exist which are capable, in addition, of splitting sucrose. The group in Sweden agrees with the concept of combined maltase-sucrase activity, but believes that both the enzymes described in Zurich are truly only one. Thus the Zurich group7. 72 envisions a total of five alpha glucosidases. All are able to hydrolyze maltose, and two have additional specific activity for sucrose, while one also splits isomaltose. The Swedish workers24 agree, except that they combine the two maltase-sucrases, and both groups name the enzymes differently. The Swiss also believe that they have discovered two beta galactosidases (lactases), while the group in Sweden has described only one. It is sufficient for the clinician to appreciate that enzymes exist with specific capabilities to hydrolyze one of the common disaccharides, except that some of them may also digest maltose, which is split by a total of four or five of the disaccharidases. It has been demonstrated that the disaccharidases are confined to the outer cell layer of the intestinal epithelium. 64 There is some disagreement as to whether the enzymes are so extremely superficial as to be restricted to the brush border of the mucosal cells37 . 64 or whether they may also be found within the cytoplasm. The enzymes are distributed in the mucosa along the entire small intestine.6 • 12 Lactase activity in the developing rabbit is maximal in the jejunum.36 In man there appears generally to be a diminution of all disaccharidase activities in the duodenum and terminal ileum with relatively uniform levels of activity for each disaccharidase throughout the remainder of the small intestine. 26 During embryonic life alpha glycosidase activities (maltase, sucrase and
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isomaltase) appear early, and by six to seven months of fetal life most have achieved levels of activity comparable to those in the adult. 6. 12. 26 Although they also make their appearance early, the beta glycosidases develop more slowly and reach normal levels of activity only at the end of the period of gestation. Certain of the multiple maltases also display delayed development, but the more rapid development of the others results in well developed maltose digestion by the time of birth. Babies born prematurely usually display decreased lactase activity during the first three days of life. 13 After infancy, levels of lactase activity usually decrease gradually, and only rarely are the levels of the first year of life maintained into adult life.6 • 12
DISORDERS OF LACTOSE DIGESTION
The disease entities related to defects in function of these disaccharidases were first suspected with the clinical descriptions by Durand39 and by Holzel,49 Within the period of less than 10 years since these reports a good deal has been written on the subject. Excellent recent reviews by Holzel,47 Prader and his group66 and Townely77 cover many of the basic aspects and discuss the disease entities. The infant who was described by Durand39 in 1958 suffered with vomiting, diarrhea and failure to thrive, and died at 15 months of age. The baby, of a consanguineous marriage which had produced an older sibling who had died of congenital anomalies, had amino-aciduria, lactosuria, and additional small quantities of other disaccharides in the urine. Subsequent authors reported additional families with infants who had amino-aciduria and lactosuria, and poor outcomes.28 In other instances patients with the same clinical picture had more fortunate outcomes on withdrawal of milk sugar from the diet.17· 42. 48 In none of these cases, however, was a direct assay of lactase activity of the intestinal mucosa performed. Lactosuria, encountered in many acute and chronic intestinal disorders such as infectious diarrhea and celiac disease, may not be regarded as evidence of an isolated congenital deficiency of lactase.66 In 1959 Holzel, Schwarz and Sutcliffe49 described two siblings who did not have lactosuria, but who suffered fermentative diarrhea and failure to thrive upon ingestion of lactose. The symptoms began at birth and were especially severe while they took human milk because of its elevated lactose content. By 1965 Prader and Auricchio66 were able to account for a total of nine similar patients, two of whom had been reported by US. 32 After feeding 3 to 5 gm. per kilogram of lactose to their infant patient, Holzel et al,49 did not observe a significant increase of blood glucose or galactose. When these sugars were fed separately, normal rises in blood sugar occurred. They concluded that the infant failed to hydrolyze the disaccharide. The test dose of disaccharide that
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they gave has been altered in similar cases to 50 gm. per square meter by Prader66 and 1 to 2 gm. per kilogram by Townley.77 These latter doses are within the range of normal infant intake with milk feedings, but they virtually always lead to diarrhea in patients with lactase deficiency. Unable to hydrolyze and absorb the lactose, it remains in the intestinal lumen of aHected persons and passes to the colon, where a • portion is excreted unchanged, the rest undergoing bacterial degradation. Liquid, frothy diarrhea results in part from fermentation and in part from the osmotic eHect of the abnormal amounts of low-molecular-weight carboxylic acids, principally lactic acid, which are being excreted.66 . 77. 83 The stool pH is consequently low. 32 . 66. 74. 83 If patients with lactase deficiency are fed sucrose or maltose, none of these abnormalities results. Direct assay of disaccharidase activity of the small intestine has moved out of the research laboratory and has been developed into a useful clinical tool in recent years. Techniques of peroral small intestinal mucosal biopsy which were introduced for morphologic studies in malabsorptive states 3 • 69 . 79 have been adapted to the clinical evaluation of patients with difficulty in digesting disaccharides. Micromethods of assay are available for evaluation of the specific enzyme activities in the small biopsy specimens. H • 19. 78 These techniques have been used to confirm diagnoses of specific enzymatic deficiencies among patients with suggestive clinical histories and abnormal disaccharide tolerance tests. After the demonstration that persistent explosive diarrhea could develop in some children as a result of lactase insufficiency, direct assays and lactose tolerance tests were carried out in a variety of clinical situations. Sunshine and Kretchmer76 investigated six infants who, after bouts of what was presumed to be acute episodes of infectious diarrhea, had vomiting, persistent fermentative diarrhea with acid stools and lactosuria, upon reintroduction of milk feedings. The relation of these symptoms to lactose ingestion was verified by demonstration of the inability of the children to hydrolyze lactose and disappearance of all symptoms on withdrawal of lactose from the diet. The authors suggest, in agreement with other observations made by the same group in animal experiments,75 that the lactosuria is due to increased absorption of lactose, which is related to the large amount of undigested lactose in the intestine. Once absorbed, the disaccharide is not normally metabolized and is excreted unchanged in the urine. Others contend66 • 77. 85 that the reason for lactosuria is absorption of the disaccharide, based less on the amount in the lumen than on the fact that the mucosa is damaged in many of these patients and permeability is therefore increased. Although direct visualization of the mucosa was not performed by Sunshine and Kretchmer, there is corollary evidence that their patients may have had such mucosal damage and generalized enzymatic defects, since some of the infants also demonstrated sucrose intolerance. The intestinal tract epithelium has a rapid turnover rate of approximately 48 hours,54 and the superi :
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ficially placed disaccharidases are consequently extremely vulnerable to any noxious influence that would interfere with normal mucosal regeneration. Prader 66 suggests that these mucosal lesions affect all the disaccharidases, but that since the lesions are often not totally disruptive to the mucosa, only the decrease in lactase activity, which is normally lower than that of the other disaccharidases, becomes clinically symptomatic. A number of other instances have been reported in which this type of disaccharidase deficiency has developed secondary to destruction of the intestinal mucosa. Infections of the gastrointestinal tract,18, 76 malnutrition and kwashiorkor,14, 18 celiac disease and sprue, 57, 59,65 and giardiasis 40 , 68 have all been reported to be associated with mucosal alterations and lactase insufficiency. Similarly, patients with extensive small bowel resections have been demonstrated to have decreased lactase function. 51 ,82 Burke16 showed that early onset of the secondary type of lesion in infants with diarrhea from other causes might be mistaken for the congenital lesion. He observed 13 infants for periods of three weeks to several months on lactose-free diets before they returned to a normal state. Fortunately, 11 of the infants had biopsy studies to document abnormalities during the symptomatic period with reversion to normal after treatment with the lactose-free diet. It is possible that the patients reported by Durand39 and Darling28 were also of this variety, since it appears that congenital alactasia is probably a permanent deficiency in which the mucosa is morphologically intact and the condition is not associated with lactosuria. Presumably Durand's and Darling's patients suffered temporary deficiencies which had begun early in life similar to those described by Holzel,48 Sunshine and Kretchmer76 and Burke. 16 Presence or absence of lactosemia and lactosuria in such patients would depend on the doses of lactose to which they were exposed and on the degree of mucosal damage. There exists the further possibility that the amino-aciduria which many of these patients display may be secondary to a toxic effect of lactose on the renal tubules and that this symptom does not represent a primary metabolic defect. Carson and Neely17 suggest that the secondary variety of lactase deficiency is also more frequently associated with vomiting, which they believe results from a "toxic" effect of lactosemia. Lactase deficiency has also been reported in situations other than those wherein morphologic mucosal abnormalities are usually expected. Cozzett020 reported lactase deficiency in association with cystic fibrosis. Since the enzyme normally decreases in activity after infancy, a number of authors have investigated the possibility that symptoms of milk intolerance and vague dyspeptic and "irritable colon" symptoms in adults might be associated with deficiencies of lactase.66 , 77 Auricchi010 demonstrated an isolated defect of lactase in intestinal mucosal specimens in three patients who had tolerated milk as infants, but not as adults, from among a total of 18 specimens secured during operations for peptic
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ulcers. Others extended these studies to demonstrate lactase deficiency in biopsy specimens or failure to hydrolyze lactose in tolerance tests, among larger groups of patients with functional problems.27 , 38, 45 In the literature associated with disaccharidase deficiencies some patients are reported to have had steatorrhea8s and some not. We did not observe this ill the patients we studied and we suggested,32, 74 in agreement with others,66.77 that the steatorrhea is a primary disorder in certain conditions associated with mucosal destruction. 14, 18, 40. 57-9. 65, 68 Secondary disaccharidase deficiencies observed in these patients are unrelated to the steatorrhea. In one report the author implies that the steatorrhea is caused by lactase insufficiency'<;1 His case is weakened, however, by the apparent onset of the steatorrhea only after a massive small bowel resection, although the lactase deficiency was apparently present earlier. The cause of vomiting in patients with lactase deficiency is unclear. Few authors other than Carson and Neely17 have suggested a possible mechanism. One might assume that since it is reported mainly in infants, the symptom may result from a reflex response to distention of the lower intestinal tract by the gas and fluid. Vomiting in newborn infants with Hirschsprung's disease is assumed to occur for this reason. Another interesting speculation is derived from a report that the rate at which ingested lactose empties from the stomach is dependent on the rate at which the disaccharide is hydrolyzed in the small intestine. 6s An interesting corollary report43 demonstrates that the too rapid emptying of disaccharides from the stomach after gastrojejunostomy imposes a burden on the disaccharide absorbing and digesting mechanism with all the resultant symptoms of disaccharidase deficiencies. It is therefore reasonable to speculate that, in the person with a normal pylorus, if upper intestinal hydrolysis of lactose were to be delayed because of enzyme deficiency, the stomach might remain filled and distended with fluid drawn in by osmotic activity of the lactose which cannot be passed into the duodenum. This gastric dilatation may be the cause of the vomiting. Summary of Terminologies and Concepts Most reviewers prefer to discuss sucrose digestion problems before tackling those associated with lactose, presumably because this makes for a somewhat more straightforward story.47,66, 77 We have chosen to present the lactase problems first precisely because the varieties of clinical problems associated with this enzyme are more numerous and they illustrate how the diagnostic investigations and classifications have arisen which serve to separate one type from another. Varying terminologies are used by different workers. Townley77 distinguishes between a disaccharide intolerance and the corresponding disaccharidase defect. The former term is applied to patients who have clinical symptoms on ingestion of the disaccharide, either
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in food or as part of a loading test, but in whom the specific disaccharidase activity in the mucosa has either not been measured or has been demonstrated to be normal. He reserves the term "disaccharidase defect" for those patients in whom direct assay has demonstrated a lowering of enzyme activity. He points out that lactase specifically may be shown to be present in low titer in the adult, although the person may not display symptoms of milk intolerance. Holze147 ,48 applies the term lactose intolerance to patients with a temporary or secondary defect of enzyme activity, and alactasia or lactase deficiency to the more permanent congenital form of enzyme defect. Prader and we have applied the term disaccharide malabsorption to patients in whom specific enzymatic deficiencies were not demonstrated. l l Prader66 cautions that we may not always be dogmatic about the meaning of a biopsy assay, in contradistinction to the more rigid implications of Townley's nomenclature. He suggests that a small biopsy may be misleading about the over-all ability of a patient to hydrolyze lactose. For example, in celiac disease the mucosal disorganization is sometimes irregular and usually affects the duodenum and upper jejunum most severely. Biopsies taken from these sites may imply virtually. no lactase activity, while the over-all intestinal capacity to tolerate and hydrolyze lactose is not remarkably impaired, He suggests that only a combination of the tolerance tests with direct assay for the specific disaccharidase, and comparisons of the ratios among all the disaccharidases, provide sufficient checks for adequate diagnoses. Patients who, in addition to lactase deficits, also display deficiencies of other disaccharidases are presumably all of the secondary variety. A few authors have implied that this generalization is not always true, but their contentions have not been clearly documented. The distorted mucosa shown in the biopsy from the very small infant described by Clark et al,19 could have developed from the anoxic episodes and stormy clinical course that the authors describe. Such a mucosa would not represent the primary defect which they suggest and is understandably associated with deficiency of more than one enzyme.
DISORDERS OF SUCROSE-ISOMALTOSE DIGESTION
Malabsorption of sucrose was first described by Weijers et al. 84 in 1960. At the time of their review in 1965, Prader and Auricchio~6 were able to account for a total of 63 reported patients, only five of whom had reached adult life before the diagnosis had been made. In virtually all cases diarrhea had begun as soon after birth as sucrose or dextrins were added to modify the cow's milk formulas, and it had disappeared when glucose or lactose was substituted. In breast-fed infants who were ingesting only lactose, the onset of the diarrhea was delayed until sucrose
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was introduced into the diet. Some of the children had therefore erroneously been thought to be suffering from allergy to cow's milk proteins. The Zurich group reported that patients with sucrase insufficiency also suffered from isomaltase insufficiency.s. 9 Since sufficient pure isomaltose is not usually available for tests of tolerance, these authors introduced testing with palatinose, a product of bacterial activity with the structure (1-6 alpha glucose-fructose), S1 similar to the linkage of isomaltose (1-6 alpha di-glucose). Among four patients they confirmed their findings with loading tests of isomaltose. s Anderson5 was the first to demonstrate directly the combined sucrase-isomaltase defect by direct assay of peroral mucosal biopsy specimens. In no instance has an isolated deficit of one or the other enzyme been demonstrated by direct assay.77 Although universally present with sucrase deficiency, the accompanying isomaltase deficit is not as great and is usually lost as the child grows older. 9. 66 By one to two years of age this natural improvement renders the problem of isomaltase deficiency of no clinical significance, and young infants have much milder diarrhea after ingestion of starches or dextrins than if comparable doses of sucrose are taken. 66 Although Prader and his groupS, 9, ,66 stress the combined sucrase-isomaltase deficiency, and should be given full credit for the startling discovery that a presumed hereditary defect should affect two enzymes simultaneously,ll it is our own impression that the isomaltase deficiency is of greater scientific than clinical importance even in infancy. Isomaltose makes up only a minor fraction of starch and dextrins. Prader and his group66 agree that despite the lowered isomaltase activities measured in the duodenal mucosa of children with sucrase deficiencies,15 most had no clinical difficulty with starch digestion. Our own excessive stress on the likely lack of clinical importance of starch malabsorption in these patients is exerted in the hope that additional children not be needlessly managed with dietary restrictions for "starch intolerance" based on limited evidence. 29 . 31 We have followed up one patient with sucrase-isomaltase deficiency who is referred to by Auricchio et alP This six-year-old youngster develops definite symptomatology with small doses of sucrose, but no clinical problems are apparent after he has ingested large amounts of starch. His mother reports this to have been true even when he was less than one year of age. Sucrase-isomaltase insufficiency is generally assumed to be congenital and hereditary in all instances. 5, 15. 66. 77 Aurricchio et a1. 9 initially suggested that the lesion was inherited as an autosomal dominant trait. More recent studies suggest that a recessive mode of transmission applies. 15 ,52 All persons in whom peroral biopsies were performed, except one, displayed the normal histology which is associated with congenital deficiencies of disaccharidases. In that exception67 the mucosal atrophy that was described reverted to normal under treatment with a sucrose-free
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diet. Two other abnormalities which are found only among patients with secondary deficiencies and are not present among patients with the congenital form of lactase deficiency, are described in association with sucrase-isomaltase deficiency, presumably always congenital. Most patients display sucrosuria, and palatinosuria after ingestion of palatinose. 15 . 66 It is suggested that malabsorption of fat may result either from accelerated transit time or from a direct effect on fat absorption caused by the excess disaccharide in the intestinal lumen .
GLUCOSE-GALACTOSE MALABSORPTION
In the course of study of an infant with presumed congenital lactase deficiency, Lindquist and Meeuwisse60 discovered that the infant had an intolerance to the monosaccharides glucose and galactose. There was also glycosuria. On a formula in which the only carbohydrate was fructose or in which carbohydrate was limited, sugar disappeared from feces and urine and diarrhea cleared. These same authors 61 . 62 have reported a total of four such patients to date. Others have been added from France,53 Australia4 and the United States. 70 Intestinal mucosal histology is normal. 4. 70 Autoradiographic studies in one patient demonstrated that the site of the transport lesion was in the mucosal cells. 70
DIAGNOSIS AND TREATMENT
Primary disaccharidase deficiency should be considered a diagnostic possibility among children with chronic or recurrent diarrhea of undetermined cause. Even when the cause has been established, persistence of diarrhea after adequate treatment may be due to secondary disaccharidase deficiency. The temporal relations between onset of diarrhea and types of sugars being ingested are more important clues to diagnosis than is the severity of symptoms, although very young infants are generally prone to more severe explosive diarrhea with resultant fluid and electrolyte losses. Fresh stools should be examined for acidity and for reducing substances. Townley77 suggests that Combistix papers (for pH and glucose) or Clinitest tablets (for reducing sugars) will suffice for screening tests on stools. We have suggested testing with pH paper on a finger cot immediately after rectal examination to circumvent the question of stool freshness and of possible loss of volatile short-chain fatty acids. 32 . 74 For any of these examinations one must be certain that the testing tablets or tapes are in contact with liquid portions of the stool, or that a small amount of distilled water is added, to ensure that the test reactions will be performed in solution.
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DISACCHARIDE INTOLERANCE
It is often possible to make a relatively firm diagnosis without further testing, if suggestive evidence of disaccharide malabsorption has been established by these simple tests and the clinical history is taken into account. N ewbom infants on breast milk or cow's milk formulas to which sucrose or dextrins have not been added must be assumed to have lactase insufficiency. Conversely, patients whose symptoms occur primarily with proprietary milk substitutes, e.g. protein hydrolysate formulas or soybean milk preparations which virtually all contain sucrose as the carbohydrate, are likely to have sucrase-isomaltase deficiency. One must be alert to the possibility of a rare case of monosaccharide malabsorption4, 53, 60-62, 70 in very young infants with diarrhea that persists despite changes which exclude each of the disaccharides. Secondary deficiencies may be suspected among children in whom a primary disease has been demonstrated and in whom persistence of acid stools or melituria is demonstrable after treatment for the underlying disease. Whenever doubt exists about diagnosis, a properly organized series of disaccharide and monosaccharide loading tests 49 ,66, 77 will usually point to the nature of the problem, and the clinical response to elimination of the presumed offending sugars will usually indicate whether correct decisions have been made. As pointed out above, in the secondary malabsorption problems, elimination of lactose alone will usually suffice to end symptoms. 16 , 66 Wherever the clinial laboratory is organized to do so, special examinations such as chromatographic identifications of fatty acids and carbohydrates in the stools and urine, and direct assay of disaccharidase activities in the intestinal mucosa,ll, 15, 19,66, 77, 78 may be performed. Treatment consists in avoidance of the offending sugar, for fixed periods of time in patients with secondary problems and for indeterminate, essentially permanent periods in patients with congenital deficiencies.
SUMMARY
The clinical syndromes and interrelations among the various conditions associated with malabsorption of carbohydrates have been described, stressing the bases on which they may be separated from one another. Congenital deficiencies of specific disaccharidases are associated with normal intestinal histology and a defect of either lactase or sucraseisomaltase production. Secondary deficiencies affect all the enzymes, mainly as a result of distortion of the mucosal architecture. Since lactase is normally present in lowest activity, it is often the only deficiency which is clinically apparent in secondary defects, even though sucrase and isomaltase activities are also lowered. In a few rare instances patients have been described with malabsorption of the monosaccharides
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glucose and galactose. The spurious entity of starch intolerance has been discussed with emphasis on the erroneous basis on which the diagnosis became popular.
REFERENCES 1. Andersen, D. H.: Celiac Syndrome; Relationship of Celiac Disease, Starch In-
tolerance and Steatorrhea. J. Pediat., 30:564, 1947. 2. Andersen, D. H., and Di Sant'Agnese, P. A.: Idiopathic Celiac Disease. I. Mode of Onset and Diagnosis. Pediatrics, 11:207, 1953. 3. Anderson, C. M.: Histological Changes in the Duodenal Mucosa in Coeliac Disease: Reversibility During Treatment with a Wheat Gluten Free Diet. Arch. Dis. Childhood, 35:419, 1960. 4. Anderson, C. M., Kerry, K. R., and Townley, R. R. W.: Inborn Defect of Intestinal Absorption of Certain Monosaccharides. Arch. Dis. Childhood, 40:1, 1965. 5. Anderson, C. M., Messer, M., Townley, R. R. W., and Freeman, M.: Intestinal Sucrase and Isomaltase Deficiency in Two Siblings. Pediatrics, 31:1003, 1963. 6. Auricchio, S., Rubino, A., and Miirset, G.: Intestinal Glycosidase Activities in the Human Embryo, Fetus, and Newborn. Pediatrics, 35:944, 1965. 7. Auricchio, S., Semenza, G., and Rubino, A.: Multiplicity of Human Intestinal Disaccharidases. II. Characterisation of the Individual Maltases. Biochim. Biophys. Acta, 96:498, 1965. 8. Aurricchio, S., Dahlqvist, A., Miirset, G., and Prader, A.: Isomaltose Intolerance Causing Decreased Ability to Utilize Dietary Starch. J. Pediat., 62:165, 1963. 9. Aurricchio, S., Prader, A., Miirset, G., and Witt, G.: Saccharoseintoleranz. Durchfall infolge hereditaren Mangels an intestinaler Saccharaseaktivitat. Helvet. Paediat. Acta, 16:483, 1961. 10. Auricchio, S., Rubino, A., Landolt, M., Semenza, G., and Prader, A.: Isolated Intestinal Lactase Deficiency in the Adult. Lancet, 2:324, 1963. 11. Auricchio, S., Rubino, A., Prader, A., Rey, J., Jos, J., Fn~zal, J., and Davidson, M.: Intestinal Glycosidase Activities in Congenital Malabsorption of Disaccharides. J. Pediat., 66:555, 1965. 12. Auricchio, S., and others: Disaccharidase Activities in Human Intestinal Mucosa. Enzymol. Biol. CUn., 3,193, 1963. 13. Boellner, S. W., Beard, A. G., and Panos, T. C.: Impairment of Intestinal Hydrolysis of Lactose in Newborn Infants. Pediatrics, 36:542, 1965. 14. Bowie, M. D., Brinkmann, E. L., and Hansen, J. D. 1..: Diarrhoea in ProteinCalorie Malnutrition. Lancet, 2:550, 1963. 15. Burgess, E. A., Levin, B., Mahalanabis, D., and Tonge, R. E.: Hereditary Sucrose Intolerance: Levels of Sucrase Activity in Jejunal Mucosa. Arch. Dis. Childhood, 39:431, 1964. 16. Burke, V., Kerry, K. R., and Anderson, C. M.: The Relationship of Dietary Lactose to Refractory Diarrhoea in Infancy. Aust. Paediat. J., 1:147, 1965. 17. Carson, N. A. J., and Neely, R. A.: Disaccharide Intolerance in Infancy. Arch. Dis. Childhood, 38:574, 1963. 18. Cevini, G., Giovannini, M., and Careddu, P.: Alterazioni della Digestione e dell'Assorbimento Intestinale dei Glucidi nei Disturbi Acuti e Cronici della Nutrizione del Lattante. Minerva Paediat., 14:831, 1962. 19. Clarke, J. T., Quillian, W., and Shwachman, H.: Chronic Diarrhea and Failure to Thrive Due to Intestinal Disaccharidase Insufficiency. PediatriCS, 34:807, 1964. 20. Cozzetto, F. J.: Intestinal Lactase Deficiency in a Patient with Cystic Fibrosis. Pediatrics, 32:228, 1963. 21. Czerny, A. D.: Des Kindes Ernahrung, ErnahrungstOrungen und Ernahrungstherapie. Leipzig, Deuticke, 1906, Vol. 1, p. 235. 22. Dahlqvist, A.: Hog Intestinal a-Glucosidases. Doctoral dissertation, Lund., 1960. 23. Idem: Pig Intestinal ,B-Glucosidase Activities. I. Relation to ,B-Galactosidase (Lactase). Biochim. Biophys. Acta, 50:55, 1961.
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24. Idem: Specificity of the Human Intestinal Disaccharidases and Implications for Hereditary Disaccharide Intolerance. J. Clin. Invest., 41:463, 1962. 25. Dahlqvist, A., and Brun, A.: A Method for the Histochemical Demonstration of Disaccharidase Activities: Application to Invertase and Trehalase in Some Animal Tissues. J. Histochem. Cytochem., 10:294, 1962. 26. Dahlqvist, A., and Lindberg, T.: Development of the Intestinal Disaccharidase and AlkalinePhosphatase Activities in the Human Foetus. Clin. Sci., 30:517, 1966. 27. Dahlqvist, A., Hammond, J. B., Crane, R K., Dunphy, J. V., and Littman, A.: Intestinal Lactase Deficiency and Lactose Intolerance in Adults. Preliminary Report. Gastroenterology, 45:488, 1963. 28. Darling, S., Mortensen, 0., and Sondergaard, G.; Lactosuria and Amino-Aciduria in Infancy. A New Inborn Error of Metabolism? Acta Paediat., 49:281, 1960. 29. Davidson, M.: Nonspecific Diarrhea; in S. S. Gellis and B. M. Kagan: Current Pediatric Therapy, 1966-1967. Philadelphia, W. B. Saunders Company, 1966, pp.256-9. 30. Davidson, M., and Bauer, C. H.: The Value of Microscopic Examination of the Stool for Extracellular Starch in the Diagnosis of Starch Intolerance. Pediatrics, 21:565, 1958. 31. Davidson, M., and Wasserman, R: The Irritable Colon of Childhood (Chronic Nonspecific Diarrhea Syndrome). J. Pediat., to be published. 32. Davidson, M., Sobel, E. H., Kugler, M. M., and Prader, A.: Intestinal Lactase Deficiency of Presumed Congenital Origin in Two Older Children. Gastroenterology, 46:737, 1964. 33. Dicke, W. K., Weijers, H. A., and van de Kamer, J. H.: Coeliac Disease. II. The Presence in Wheat of a Factor Having a Deleterious Effect in Cases of Coeliac Disease. Acta Paediat., 42:97, 1953. 34. Di Sant'Agnese, P. A.: Intestinal Malabsorption; in W. E. Nelson: Textbook of Pediatrics. 8th ed. Philadelphia, W. B. Saunders Company, 1964, pp. 720-30. 35. Idem: Malabsorption Syndromes (Celiac Syndrome); in S. S. Gellis and B. M. Kagan: Current Pediatric Therapy, 1966-1967. Philadelphia, W. B. Saunders Company, pp. 307-313. 36. Doell, R. G., and Kretchmer, N.: Studies of Small Intestine During Development. I. Distribution and Activity of ,a-Galactosidase. Biochim. Biophys. Acta, 62:353, 1962. 37. Doell, R G., Rosen, G., and Kretchmer, N.: Immunochemical Studies of Intestinal Disaccharidases During Normal and Precocious Development. Proc. Nat. Acad. Sci., 54:1268, 1965. 38. Dunphy, J. V., and others: Intestinal Lactase Deficit in Adults. Gastroenterology, 49:12, 1965. 39. Durand, P.: Lactosuria Idiopathica in una Paziente con Diarrea Cronica ed Acidosi. Minerva pediat., 10:706, 1958. 40. Durand, P., and LaMedica, G. M. Disaccharide Intolerance. Helv. Paediat. Acta, 17:395, 1962. 41. Finkelstein, H., and Meyer, L. F.: Zur Technik und Indikation der Ernahrung mit Eiweissmilch. Miinchen. med. Wchnschr., 58:340, 1911. 42. Gerritsen, T., LemH, L., Ptacek, L. J., and Waisman, H. A.: The Presence of Lactulose in the Urine of Infants with Lactosuria. Pediatrics, 32:1033, 1963. 43. Gryboski, J. D., Thayer, W. R, Jr., Gryboski, W. A., Gabrielson, I. W., and Spiro, H. M. A Defect in Disaccharide Metabolism After Gastrojejunostomy. New England J. Med., 268:78, 1963. 44. Haas, S. V., and Haas, M. P.: Management of Celiac Disease. Philadelphia, J. B. Lippincott Company, 1951. 45. Haemmerli, U. P., and others: Acquired Milk Intolerance in the Adult Caused by Lactose Malabsorption Due to a Selective Deficiency of Intestinal Lactase Activity. Am.]. Med., 38:7,1965. 46. Herter, C. A.: On Infantilism from Chronic Intestinal Infection. New York, Macmillan Company, 1908. 47. Holzel, A.: Development of Intestinal Enzyme Systems and Its Relation to Diarrhea. PEDIAT. CUN. N. AMER., 12:635, 1965.
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48. Holzel, A., Mereu, T., and Thomson, M. L.: Severe Lactose Intolerance in Infancy. Lancet, 2:1346,1962. 49. Holzel, A., Schwarz, V., and Sutcliffe, K. W.: Defective Lactose Absorption Causing Malnutrition in Infancy. Lancet, 1:1126, 1959 . 50. Howland, J.: Prolonged Intolerance to Carbohydrates. Tr. Amer. Pediat. Soc., 33:11, 1921. 51. Kern, F., Jr., Struthers, J. E., and Attwood, W. L.: Lactose Intolerance as a Cause of Steatorrhea in an Adult. Gastroenterology, 45:477, 1963. 52. Kerry, K. R., and Townley, R. R. W.: Genetic Aspects of Sucrase-Isomaltase Deficiency. Aust. Paediat. ]., 1:223, 1965. 53. LaPlane, R., and others: L'intolerance aux sucres it transfert intestinal actif: Ses rapports avec l'intolerance au lactose et Ie syndrome coeliaque. Arch. Frang. Pediat., 19:895, 1962. 54. Laster, L., and Ingelfinger, F. J. Intestinal Absorption-Aspects of Structure, Function and Disease of the Small-Intestine Mucosa. New England]. Med., 264:1138, 1961. 55. Launiala, K., Perheentupa, J., Visakorpi, J., and Hallman, N.: Disaccharidases of Intestinal Mucosa in a Patient with Sucrose Intolerance. Pediatrics, 34:615, 1964. 56. Leblond, C. P., and Messier, B.: Renewal of Chief Cells and Goblet Cells in Small Intestine as Shown by Radioautography After Injection of Thymidine-H3 into Mice. Anat. Rec., 132:247, 1958. 57. Lifshitz, F., and Holman, G.: Familial Celiac Disease with Intestinal Disaccharidase Deficiencies. Am. J. Dig. Dis., 11:377, 1966. 58. Idem: Disaccharidase Deficiencies with Steatorrhea. ]. Pediat., 64:34, 1964. 59. Lifshitz, F., Klotz, A. P., and Holman, G. H.: Intestinal Disaccharidase Deficiencies in Gluten-Sensitive Enteropathy. Am. ]. Dig. Dis., 10:47, 1965. 60. Lindquist, B., and Meeuwisse, G. W.: Chronic Diarrhoea Caused by Monosaccharide Malabsorption. Acta Paediat., 51:674,1962. 61. Idem: Intestinal Transport of Monosaccharides in Generalized and Selective Malabsorption. Acta Paediat., 146:110,1963. 62. Lindquist, B., Meeuwisse, G. W., and Melin, K.: Osmotic Diarrhoea in Genetically Transmitted Glucose-Galactose Malabsorption. Acta Paediat., 52:217, 1963. 63. Matsui, M.: Study on the Absorption of Carbohydrates from the Alimentary Tract of Infant, Especially of Lactose. Kobe J. Med. Sci., 5:243, 1960. 64. Miller, D., and Crane, R. K.: The Digestive Function of the Epithelium of the Small Intestine. II. Localization of Disaccharide Hydrolysis in the Isolated Brush Border of the Intestinal Epithelial Cells. Biochim. Biophys. Acta, 52:293, 1961. 65. Plotkin, G. R., and Isselbacher, K. J.: Secondary Disaccharidase Deficiency in Adult Celiac Disease (Nontropical Sprue) and Other Malabsorption States. New England J. Med., 271:1033, 1964. 66. Prader, A., and Auricchio, S.: Defects of Intestinal Disaccharide Absorption. Ann. Rev. Med., 16:345, 1965. 67. Rey, J., Frezal, J., Jos, J., Bauche, P., and Lamy M.: Diarrhee par trouble de l'hydrolyse intestinale du saccharose, du maltose et de l'isomaltose. Arch. Frang. Pediat., 20:381, 1963. 68. Rossi, E., and Royer, P.: Les diarrhees chroniques par intolerance des disaccharides. Praxis, 52:1479,1963. 69. Sakula, J., and Shiner, M.: Coeliac Disease with Atrophy of the Small Intestine Mucosa. Lancet, 2:876,1957. 70. Schneider, A. J., Kinter, W. B., and Stirling, C. E.: Glucose-Galactose Malabsorption. Report of a Case with Autoradiographic Studies of a Mucosal Biopsy. New England J. Med., 274:305, 1966. 71. Semenza, G., and Auricchio, S.: Chromatographic Separation of Human Intestinal Disaccharidases. Biochim. Biophys. Acta, 65:172, 1962. 72. Semenza, G., Auricchio, S., and Rubino, A.: Multiplicity of Human Intestinal Disaccharidases. I. Chromatographic Separation of Maltases and of Two Lactases. Biochim. Biophys. Acta, 96:487, 1965. 73. Simchen, H.: Studien tiber Mehlverdauung beim Saugling. Arch. Kinderh., 75:6, 1924.
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74. Sobel, E., Davidson, M., Kugler, M. M., Zuppinger, K. A., Yu-Fent Hsu, L., and Prader, A.: Growth Retardation Associated with Intestinal Lactase Deficiency. J. Pediat., 63:731, 1963. 75. Sterk, V. V., and Kretchmer, N.: Studies of Small Intestine During Development. IV. Digestion of Lactose as Related to Lactosuria in the Rabbit. Pediatrics, 34: 609,1964. 76. Sunshine, P., and Kretchmer, N.: Studies of Small Intestine During Development. III. Infantile Diarrhea Associated with Intolerance to Disaccharides. PediatriCS, 34:3B, 1964. 77. Townley, R. R. W.: Disaccharidase Deficiency in Infancy and Childhood. Pediatrics, 3B:127, 1966. 7B. Townley, R. R. W., Khaw, K. T., and Shwachman, H.: Quantitative Assay of Disaccharidase Activities of Small Intestinal Mucosal Biopsy Specimens in Infancy and Childhood. Pediatrics, 36:911, 1965. 79. Trier, J. 5., and Rubin, C. E.: Electron Microscopy of the Small Intestine: A Review. Gastroenterology, 49:574, 1965. BO. Van de Kamer, J. H., Weijers, H. A., and Dicke, W. K.: Coeliac Disease. IV. An Investigation Into the Injurious Constituents of Wheat in Connection with Their Action on Patients with Coeliac Disease. Acta Paediat., 42:223, 1953. B1. Weidenhagen, R., and Lorenz, S.: Palatinose (6- [a-Glucopyranosidol Fructofuranose), ein neues bakterielles Umwandlungsproduckt der Saccharose. Ztschr. Zuckerindustr., 7:553,1957. B2. Weijers, H. A., and van de Kamer, J. H.: Diarrhoea Caused by the Deficiency of Sugar-Splitting Enzymes. Acta Paediat., 51:371, 1962. 83. Weijers, H. A., van de Kamer, J. H., Dicke, W. K., and Ijsseling, J.: Diarrhoea Caused by Deficiency of Sugar Splitting Enzymes. Acta Paediat., 50:55, 1961. 84. Weijers, H. A., van de Kamer, J. H. Mossel, D. A. A., and Dicke, W. K.: Diarrhoea Caused by Deficiency of Sugar Splitting Enzymes. Lancet, 2:296, 1960. 85. Weser, E., and Sleisenger, M. H.: Lactosuria and Lactase Deficiency in Adult Celiac Disease. Gastroenterology, 48:571, 1965. Bronx-Lebanon Hospital Center 1650 Grand Concourse Bronx, New York 10457
Some pediatricians are confused that intense interest has developed during the last decade in clinical syndromes associated with maHunctions in digestion and assimilation of sugars. To them these supposedly new conditions represent variations of an old entity, starch intolerance. This review would be incomplete if these relationships were not clarified at the outset. The concept of starch intolerance can be traced to misinterpretations of the meaning of the observation by Herter46 that the first cases of celiac disease seen in this country appeared to be made worse upon ingestion of certain starchy foods and to reports by European workers that infants with diarrhea sometimes did not tolerate carbohydrates well.41 In his presidential address to the American Pediatric Society in 1921, John Howland50 summarized the deleterious role of carbohydrates in infants with diarrhea. He recognized that the amount of sugar ingested could make a difference in symptomatology and anticipated current speculations that this dose phenomenon is related to osmotic activity of undigested sugar particles. He classified infants who had difficulties with ingested carbohydrates into those congenitally affected, those with a temporary defect following diarrhea, and others with a prolonged course of chronic diarrhea. Unfortunately, despite Howland's almost prophetic allusion to the role of disaccharides in the problem, most of his discourse was concerned with starch intolerance. Herter's observation about the deleterious effect of some starchy foods made so vivid an impression that Howland and a number of. equally careful later workers all displayed utter disregard for the fact that Herter4 6 had indicated that the .problem occurred only with some starchy foods, but that other starchy foods were well tolerated. From the Bronx-Lebanon Hospital Center and Bronx Municipal Hospital Center, Albert Einstein College of Medicine, Bronx, New York. Preparation of this review and of any original observations referred to herein was made possible in part by support of Public Health Service Grants A~3432 from the National Institute of Arthritis and Metabolic Disease, and HD-02032 from the National Institute of Child Health and Human Development.
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It was not until the classic observations of Dicke, Weijers and Van de Kamer33 , 80 with regard to gluten, and subsequent demonstrations that gluten-induced enteropathy is associated with specific mucosallesions,3,69,79 that the correct meaning of Herter's brilliant clinical report became clear. Herter46 had not suggested that starch itself played a role, but carefully referred only to starchy foods. Nevertheless, in the 40 years between his report and that of the Dutch workers,33, 80 pediatricians focused their attentions on starch. Andersen2 reported that levels of amylase were below normal in children with "starch intolerance." In classifications of the celiac syndrome which shel proposed and which were agreed to by others,44 impairment of starch digestion was regarded as the precursor to fat intolerance. Microscopic examinations of stools for extracellular starch granules, introduced during an earlier period of descriptive pediatrics,21, 73 became the standard "scientific" test by which many children with persistent loose stools were labeled as intolerant to starch. This presumed disease was assumed to lead to malabsorption of fat if patients with starch granules in their stools were not kept on fat-free diets. In 1958 we demonstrated that microscopic examination for starch in the stool has no significance, and that diagnosis of "starch intolerance" certainly cannot be made this way.30 More recently we have indicated our conviction that children with the clinical picture usually referred to as starch intolerance are not suffering from such a condition, if indeed the entity exists at all.31 Nevertheless "mild starch intolerance" and "mild gluten intolerance" continue to be included in various classifications of malabsorptive syndromes.34 ,35 As a result, many children are unnecessarily treated with the high protein, low fat, low starch diets commonly prescribed for "starch intolerance."l, 44 In a number of instances, failure to respond results in additional restrictions of gluten-containing foods, despite failure to demonstrate the characteristic lesion of gluten-induced enteropathy. Our purpose in beginning the current discussion with a recount of the nebulous entity of "starch intolerance" is only partIy to establish the historical relations between a possible disorder of polysaccharide digestion and those of monosaccharides and disaccharides. A more important function would be ful:6.llment of our hope that dietary manipulations will be made only in patients in whom they are indicated. It would be a crushing blow if, as a result of something we wrote, children who had been treated with needless restrictions would suffer additional privation because of unindicated withdrawals of milk or simple sugars from their diets.
Physiology
It is useful to review briefly the physiology of carbohydrate assimilation before discussing the diseases associated with defects in digestion and absorption of simple carbohydrates. Salivary and pancreatic amylase digestion of starch and glycogen results in splitting of more than 90 per
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cent of these substrates to maltose (1-4 alpha-linked di-glucose) and the remainder into isomaltose (1-6 alpha -linked di-glucose ), which comes from the branching points of chains in the polysaccharide structures. Maltose, isomaltose and two disaccharides which occur naturally, sucrose (cane sugar, 1-2 alpha-linked glucose-fructose) and lactose (milk sugar, 1-4 beta-linked galactose-glucose), together with other rare disaccharides, are absorbed intact into the mucosal layer of the small intestine, where they are hydrolyzed by specific disaccharidases into their component monosaccharides. Dahlqvist, who pioneered in the separation of the disaccharidases of the intestinal mucosa, characterized them first in hog mucosa22 • 23 and then in human beings from surgical specimens. 24 He separated the enzymes by selective heat inactivation; others added gel filtration chromatography.7. 71. 72 As a result of these different methods of separation and characterization, the group in Sweden24 and the group in Zurich7 • 72 have arrived at slightly different classifications for the enzymes. It has been suggested that some of these presumed differences may be artifactual results of the separation techniques. 55 The main elements, however, of both classifications are not dissimilar. Each group agrees that two maltases are specific only for maltose and that a third maltase hydrolyzes isomaltose as well. According to the Swiss, two additional maltases exist which are capable, in addition, of splitting sucrose. The group in Sweden agrees with the concept of combined maltase-sucrase activity, but believes that both the enzymes described in Zurich are truly only one. Thus the Zurich group7. 72 envisions a total of five alpha glucosidases. All are able to hydrolyze maltose, and two have additional specific activity for sucrose, while one also splits isomaltose. The Swedish workers24 agree, except that they combine the two maltase-sucrases, and both groups name the enzymes differently. The Swiss also believe that they have discovered two beta galactosidases (lactases), while the group in Sweden has described only one. It is sufficient for the clinician to appreciate that enzymes exist with specific capabilities to hydrolyze one of the common disaccharides, except that some of them may also digest maltose, which is split by a total of four or five of the disaccharidases. It has been demonstrated that the disaccharidases are confined to the outer cell layer of the intestinal epithelium. 64 There is some disagreement as to whether the enzymes are so extremely superficial as to be restricted to the brush border of the mucosal cells37 . 64 or whether they may also be found within the cytoplasm. The enzymes are distributed in the mucosa along the entire small intestine.6 • 12 Lactase activity in the developing rabbit is maximal in the jejunum.36 In man there appears generally to be a diminution of all disaccharidase activities in the duodenum and terminal ileum with relatively uniform levels of activity for each disaccharidase throughout the remainder of the small intestine. 26 During embryonic life alpha glycosidase activities (maltase, sucrase and
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isomaltase) appear early, and by six to seven months of fetal life most have achieved levels of activity comparable to those in the adult. 6. 12. 26 Although they also make their appearance early, the beta glycosidases develop more slowly and reach normal levels of activity only at the end of the period of gestation. Certain of the multiple maltases also display delayed development, but the more rapid development of the others results in well developed maltose digestion by the time of birth. Babies born prematurely usually display decreased lactase activity during the first three days of life. 13 After infancy, levels of lactase activity usually decrease gradually, and only rarely are the levels of the first year of life maintained into adult life.6 • 12
DISORDERS OF LACTOSE DIGESTION
The disease entities related to defects in function of these disaccharidases were first suspected with the clinical descriptions by Durand39 and by Holzel,49 Within the period of less than 10 years since these reports a good deal has been written on the subject. Excellent recent reviews by Holzel,47 Prader and his group66 and Townely77 cover many of the basic aspects and discuss the disease entities. The infant who was described by Durand39 in 1958 suffered with vomiting, diarrhea and failure to thrive, and died at 15 months of age. The baby, of a consanguineous marriage which had produced an older sibling who had died of congenital anomalies, had amino-aciduria, lactosuria, and additional small quantities of other disaccharides in the urine. Subsequent authors reported additional families with infants who had amino-aciduria and lactosuria, and poor outcomes.28 In other instances patients with the same clinical picture had more fortunate outcomes on withdrawal of milk sugar from the diet.17· 42. 48 In none of these cases, however, was a direct assay of lactase activity of the intestinal mucosa performed. Lactosuria, encountered in many acute and chronic intestinal disorders such as infectious diarrhea and celiac disease, may not be regarded as evidence of an isolated congenital deficiency of lactase.66 In 1959 Holzel, Schwarz and Sutcliffe49 described two siblings who did not have lactosuria, but who suffered fermentative diarrhea and failure to thrive upon ingestion of lactose. The symptoms began at birth and were especially severe while they took human milk because of its elevated lactose content. By 1965 Prader and Auricchio66 were able to account for a total of nine similar patients, two of whom had been reported by US. 32 After feeding 3 to 5 gm. per kilogram of lactose to their infant patient, Holzel et al,49 did not observe a significant increase of blood glucose or galactose. When these sugars were fed separately, normal rises in blood sugar occurred. They concluded that the infant failed to hydrolyze the disaccharide. The test dose of disaccharide that
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they gave has been altered in similar cases to 50 gm. per square meter by Prader66 and 1 to 2 gm. per kilogram by Townley.77 These latter doses are within the range of normal infant intake with milk feedings, but they virtually always lead to diarrhea in patients with lactase deficiency. Unable to hydrolyze and absorb the lactose, it remains in the intestinal lumen of aHected persons and passes to the colon, where a • portion is excreted unchanged, the rest undergoing bacterial degradation. Liquid, frothy diarrhea results in part from fermentation and in part from the osmotic eHect of the abnormal amounts of low-molecular-weight carboxylic acids, principally lactic acid, which are being excreted.66 . 77. 83 The stool pH is consequently low. 32 . 66. 74. 83 If patients with lactase deficiency are fed sucrose or maltose, none of these abnormalities results. Direct assay of disaccharidase activity of the small intestine has moved out of the research laboratory and has been developed into a useful clinical tool in recent years. Techniques of peroral small intestinal mucosal biopsy which were introduced for morphologic studies in malabsorptive states 3 • 69 . 79 have been adapted to the clinical evaluation of patients with difficulty in digesting disaccharides. Micromethods of assay are available for evaluation of the specific enzyme activities in the small biopsy specimens. H • 19. 78 These techniques have been used to confirm diagnoses of specific enzymatic deficiencies among patients with suggestive clinical histories and abnormal disaccharide tolerance tests. After the demonstration that persistent explosive diarrhea could develop in some children as a result of lactase insufficiency, direct assays and lactose tolerance tests were carried out in a variety of clinical situations. Sunshine and Kretchmer76 investigated six infants who, after bouts of what was presumed to be acute episodes of infectious diarrhea, had vomiting, persistent fermentative diarrhea with acid stools and lactosuria, upon reintroduction of milk feedings. The relation of these symptoms to lactose ingestion was verified by demonstration of the inability of the children to hydrolyze lactose and disappearance of all symptoms on withdrawal of lactose from the diet. The authors suggest, in agreement with other observations made by the same group in animal experiments,75 that the lactosuria is due to increased absorption of lactose, which is related to the large amount of undigested lactose in the intestine. Once absorbed, the disaccharide is not normally metabolized and is excreted unchanged in the urine. Others contend66 • 77. 85 that the reason for lactosuria is absorption of the disaccharide, based less on the amount in the lumen than on the fact that the mucosa is damaged in many of these patients and permeability is therefore increased. Although direct visualization of the mucosa was not performed by Sunshine and Kretchmer, there is corollary evidence that their patients may have had such mucosal damage and generalized enzymatic defects, since some of the infants also demonstrated sucrose intolerance. The intestinal tract epithelium has a rapid turnover rate of approximately 48 hours,54 and the superi :
.1
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ficially placed disaccharidases are consequently extremely vulnerable to any noxious influence that would interfere with normal mucosal regeneration. Prader 66 suggests that these mucosal lesions affect all the disaccharidases, but that since the lesions are often not totally disruptive to the mucosa, only the decrease in lactase activity, which is normally lower than that of the other disaccharidases, becomes clinically symptomatic. A number of other instances have been reported in which this type of disaccharidase deficiency has developed secondary to destruction of the intestinal mucosa. Infections of the gastrointestinal tract,18, 76 malnutrition and kwashiorkor,14, 18 celiac disease and sprue, 57, 59,65 and giardiasis 40 , 68 have all been reported to be associated with mucosal alterations and lactase insufficiency. Similarly, patients with extensive small bowel resections have been demonstrated to have decreased lactase function. 51 ,82 Burke16 showed that early onset of the secondary type of lesion in infants with diarrhea from other causes might be mistaken for the congenital lesion. He observed 13 infants for periods of three weeks to several months on lactose-free diets before they returned to a normal state. Fortunately, 11 of the infants had biopsy studies to document abnormalities during the symptomatic period with reversion to normal after treatment with the lactose-free diet. It is possible that the patients reported by Durand39 and Darling28 were also of this variety, since it appears that congenital alactasia is probably a permanent deficiency in which the mucosa is morphologically intact and the condition is not associated with lactosuria. Presumably Durand's and Darling's patients suffered temporary deficiencies which had begun early in life similar to those described by Holzel,48 Sunshine and Kretchmer76 and Burke. 16 Presence or absence of lactosemia and lactosuria in such patients would depend on the doses of lactose to which they were exposed and on the degree of mucosal damage. There exists the further possibility that the amino-aciduria which many of these patients display may be secondary to a toxic effect of lactose on the renal tubules and that this symptom does not represent a primary metabolic defect. Carson and Neely17 suggest that the secondary variety of lactase deficiency is also more frequently associated with vomiting, which they believe results from a "toxic" effect of lactosemia. Lactase deficiency has also been reported in situations other than those wherein morphologic mucosal abnormalities are usually expected. Cozzett020 reported lactase deficiency in association with cystic fibrosis. Since the enzyme normally decreases in activity after infancy, a number of authors have investigated the possibility that symptoms of milk intolerance and vague dyspeptic and "irritable colon" symptoms in adults might be associated with deficiencies of lactase.66 , 77 Auricchi010 demonstrated an isolated defect of lactase in intestinal mucosal specimens in three patients who had tolerated milk as infants, but not as adults, from among a total of 18 specimens secured during operations for peptic
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ii
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ulcers. Others extended these studies to demonstrate lactase deficiency in biopsy specimens or failure to hydrolyze lactose in tolerance tests, among larger groups of patients with functional problems.27 , 38, 45 In the literature associated with disaccharidase deficiencies some patients are reported to have had steatorrhea8s and some not. We did not observe this ill the patients we studied and we suggested,32, 74 in agreement with others,66.77 that the steatorrhea is a primary disorder in certain conditions associated with mucosal destruction. 14, 18, 40. 57-9. 65, 68 Secondary disaccharidase deficiencies observed in these patients are unrelated to the steatorrhea. In one report the author implies that the steatorrhea is caused by lactase insufficiency'<;1 His case is weakened, however, by the apparent onset of the steatorrhea only after a massive small bowel resection, although the lactase deficiency was apparently present earlier. The cause of vomiting in patients with lactase deficiency is unclear. Few authors other than Carson and Neely17 have suggested a possible mechanism. One might assume that since it is reported mainly in infants, the symptom may result from a reflex response to distention of the lower intestinal tract by the gas and fluid. Vomiting in newborn infants with Hirschsprung's disease is assumed to occur for this reason. Another interesting speculation is derived from a report that the rate at which ingested lactose empties from the stomach is dependent on the rate at which the disaccharide is hydrolyzed in the small intestine. 6s An interesting corollary report43 demonstrates that the too rapid emptying of disaccharides from the stomach after gastrojejunostomy imposes a burden on the disaccharide absorbing and digesting mechanism with all the resultant symptoms of disaccharidase deficiencies. It is therefore reasonable to speculate that, in the person with a normal pylorus, if upper intestinal hydrolysis of lactose were to be delayed because of enzyme deficiency, the stomach might remain filled and distended with fluid drawn in by osmotic activity of the lactose which cannot be passed into the duodenum. This gastric dilatation may be the cause of the vomiting. Summary of Terminologies and Concepts Most reviewers prefer to discuss sucrose digestion problems before tackling those associated with lactose, presumably because this makes for a somewhat more straightforward story.47,66, 77 We have chosen to present the lactase problems first precisely because the varieties of clinical problems associated with this enzyme are more numerous and they illustrate how the diagnostic investigations and classifications have arisen which serve to separate one type from another. Varying terminologies are used by different workers. Townley77 distinguishes between a disaccharide intolerance and the corresponding disaccharidase defect. The former term is applied to patients who have clinical symptoms on ingestion of the disaccharide, either
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in food or as part of a loading test, but in whom the specific disaccharidase activity in the mucosa has either not been measured or has been demonstrated to be normal. He reserves the term "disaccharidase defect" for those patients in whom direct assay has demonstrated a lowering of enzyme activity. He points out that lactase specifically may be shown to be present in low titer in the adult, although the person may not display symptoms of milk intolerance. Holze147 ,48 applies the term lactose intolerance to patients with a temporary or secondary defect of enzyme activity, and alactasia or lactase deficiency to the more permanent congenital form of enzyme defect. Prader and we have applied the term disaccharide malabsorption to patients in whom specific enzymatic deficiencies were not demonstrated. l l Prader66 cautions that we may not always be dogmatic about the meaning of a biopsy assay, in contradistinction to the more rigid implications of Townley's nomenclature. He suggests that a small biopsy may be misleading about the over-all ability of a patient to hydrolyze lactose. For example, in celiac disease the mucosal disorganization is sometimes irregular and usually affects the duodenum and upper jejunum most severely. Biopsies taken from these sites may imply virtually. no lactase activity, while the over-all intestinal capacity to tolerate and hydrolyze lactose is not remarkably impaired, He suggests that only a combination of the tolerance tests with direct assay for the specific disaccharidase, and comparisons of the ratios among all the disaccharidases, provide sufficient checks for adequate diagnoses. Patients who, in addition to lactase deficits, also display deficiencies of other disaccharidases are presumably all of the secondary variety. A few authors have implied that this generalization is not always true, but their contentions have not been clearly documented. The distorted mucosa shown in the biopsy from the very small infant described by Clark et al,19 could have developed from the anoxic episodes and stormy clinical course that the authors describe. Such a mucosa would not represent the primary defect which they suggest and is understandably associated with deficiency of more than one enzyme.
DISORDERS OF SUCROSE-ISOMALTOSE DIGESTION
Malabsorption of sucrose was first described by Weijers et al. 84 in 1960. At the time of their review in 1965, Prader and Auricchio~6 were able to account for a total of 63 reported patients, only five of whom had reached adult life before the diagnosis had been made. In virtually all cases diarrhea had begun as soon after birth as sucrose or dextrins were added to modify the cow's milk formulas, and it had disappeared when glucose or lactose was substituted. In breast-fed infants who were ingesting only lactose, the onset of the diarrhea was delayed until sucrose
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was introduced into the diet. Some of the children had therefore erroneously been thought to be suffering from allergy to cow's milk proteins. The Zurich group reported that patients with sucrase insufficiency also suffered from isomaltase insufficiency.s. 9 Since sufficient pure isomaltose is not usually available for tests of tolerance, these authors introduced testing with palatinose, a product of bacterial activity with the structure (1-6 alpha glucose-fructose), S1 similar to the linkage of isomaltose (1-6 alpha di-glucose). Among four patients they confirmed their findings with loading tests of isomaltose. s Anderson5 was the first to demonstrate directly the combined sucrase-isomaltase defect by direct assay of peroral mucosal biopsy specimens. In no instance has an isolated deficit of one or the other enzyme been demonstrated by direct assay.77 Although universally present with sucrase deficiency, the accompanying isomaltase deficit is not as great and is usually lost as the child grows older. 9. 66 By one to two years of age this natural improvement renders the problem of isomaltase deficiency of no clinical significance, and young infants have much milder diarrhea after ingestion of starches or dextrins than if comparable doses of sucrose are taken. 66 Although Prader and his groupS, 9, ,66 stress the combined sucrase-isomaltase deficiency, and should be given full credit for the startling discovery that a presumed hereditary defect should affect two enzymes simultaneously,ll it is our own impression that the isomaltase deficiency is of greater scientific than clinical importance even in infancy. Isomaltose makes up only a minor fraction of starch and dextrins. Prader and his group66 agree that despite the lowered isomaltase activities measured in the duodenal mucosa of children with sucrase deficiencies,15 most had no clinical difficulty with starch digestion. Our own excessive stress on the likely lack of clinical importance of starch malabsorption in these patients is exerted in the hope that additional children not be needlessly managed with dietary restrictions for "starch intolerance" based on limited evidence. 29 . 31 We have followed up one patient with sucrase-isomaltase deficiency who is referred to by Auricchio et alP This six-year-old youngster develops definite symptomatology with small doses of sucrose, but no clinical problems are apparent after he has ingested large amounts of starch. His mother reports this to have been true even when he was less than one year of age. Sucrase-isomaltase insufficiency is generally assumed to be congenital and hereditary in all instances. 5, 15. 66. 77 Aurricchio et a1. 9 initially suggested that the lesion was inherited as an autosomal dominant trait. More recent studies suggest that a recessive mode of transmission applies. 15 ,52 All persons in whom peroral biopsies were performed, except one, displayed the normal histology which is associated with congenital deficiencies of disaccharidases. In that exception67 the mucosal atrophy that was described reverted to normal under treatment with a sucrose-free
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diet. Two other abnormalities which are found only among patients with secondary deficiencies and are not present among patients with the congenital form of lactase deficiency, are described in association with sucrase-isomaltase deficiency, presumably always congenital. Most patients display sucrosuria, and palatinosuria after ingestion of palatinose. 15 . 66 It is suggested that malabsorption of fat may result either from accelerated transit time or from a direct effect on fat absorption caused by the excess disaccharide in the intestinal lumen .
GLUCOSE-GALACTOSE MALABSORPTION
In the course of study of an infant with presumed congenital lactase deficiency, Lindquist and Meeuwisse60 discovered that the infant had an intolerance to the monosaccharides glucose and galactose. There was also glycosuria. On a formula in which the only carbohydrate was fructose or in which carbohydrate was limited, sugar disappeared from feces and urine and diarrhea cleared. These same authors 61 . 62 have reported a total of four such patients to date. Others have been added from France,53 Australia4 and the United States. 70 Intestinal mucosal histology is normal. 4. 70 Autoradiographic studies in one patient demonstrated that the site of the transport lesion was in the mucosal cells. 70
DIAGNOSIS AND TREATMENT
Primary disaccharidase deficiency should be considered a diagnostic possibility among children with chronic or recurrent diarrhea of undetermined cause. Even when the cause has been established, persistence of diarrhea after adequate treatment may be due to secondary disaccharidase deficiency. The temporal relations between onset of diarrhea and types of sugars being ingested are more important clues to diagnosis than is the severity of symptoms, although very young infants are generally prone to more severe explosive diarrhea with resultant fluid and electrolyte losses. Fresh stools should be examined for acidity and for reducing substances. Townley77 suggests that Combistix papers (for pH and glucose) or Clinitest tablets (for reducing sugars) will suffice for screening tests on stools. We have suggested testing with pH paper on a finger cot immediately after rectal examination to circumvent the question of stool freshness and of possible loss of volatile short-chain fatty acids. 32 . 74 For any of these examinations one must be certain that the testing tablets or tapes are in contact with liquid portions of the stool, or that a small amount of distilled water is added, to ensure that the test reactions will be performed in solution.
103
DISACCHARIDE INTOLERANCE
It is often possible to make a relatively firm diagnosis without further testing, if suggestive evidence of disaccharide malabsorption has been established by these simple tests and the clinical history is taken into account. N ewbom infants on breast milk or cow's milk formulas to which sucrose or dextrins have not been added must be assumed to have lactase insufficiency. Conversely, patients whose symptoms occur primarily with proprietary milk substitutes, e.g. protein hydrolysate formulas or soybean milk preparations which virtually all contain sucrose as the carbohydrate, are likely to have sucrase-isomaltase deficiency. One must be alert to the possibility of a rare case of monosaccharide malabsorption4, 53, 60-62, 70 in very young infants with diarrhea that persists despite changes which exclude each of the disaccharides. Secondary deficiencies may be suspected among children in whom a primary disease has been demonstrated and in whom persistence of acid stools or melituria is demonstrable after treatment for the underlying disease. Whenever doubt exists about diagnosis, a properly organized series of disaccharide and monosaccharide loading tests 49 ,66, 77 will usually point to the nature of the problem, and the clinical response to elimination of the presumed offending sugars will usually indicate whether correct decisions have been made. As pointed out above, in the secondary malabsorption problems, elimination of lactose alone will usually suffice to end symptoms. 16 , 66 Wherever the clinial laboratory is organized to do so, special examinations such as chromatographic identifications of fatty acids and carbohydrates in the stools and urine, and direct assay of disaccharidase activities in the intestinal mucosa,ll, 15, 19,66, 77, 78 may be performed. Treatment consists in avoidance of the offending sugar, for fixed periods of time in patients with secondary problems and for indeterminate, essentially permanent periods in patients with congenital deficiencies.
SUMMARY
The clinical syndromes and interrelations among the various conditions associated with malabsorption of carbohydrates have been described, stressing the bases on which they may be separated from one another. Congenital deficiencies of specific disaccharidases are associated with normal intestinal histology and a defect of either lactase or sucraseisomaltase production. Secondary deficiencies affect all the enzymes, mainly as a result of distortion of the mucosal architecture. Since lactase is normally present in lowest activity, it is often the only deficiency which is clinically apparent in secondary defects, even though sucrase and isomaltase activities are also lowered. In a few rare instances patients have been described with malabsorption of the monosaccharides
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glucose and galactose. The spurious entity of starch intolerance has been discussed with emphasis on the erroneous basis on which the diagnosis became popular.
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