Lactose was initially implicated as a cause of diarrhea by Jacobi around the turn of the century. l However, it was not until Holzel's observations in 1959 on lactose intolerance in infants that interest focussed on this issue.2 Since that time the large body of literature generated on the subject has also spawned considerable controversy and a confusing nomenclature for the pediatric practitioner. In this article an attempt is made to clarify the confusion via a brief review of some developmental aspects of lactose metabolism, analysis of the varying clinical manifestations which follow disordered metabolism after lactose ingestion, relationship of diarrhea to other symptoms, and description of the methods of diagnosis and management of patients with lactose intolerance.
Following its ingestion, lactose, a disaccharide composed of the monosaccharides glucose and galactose in a 1-4 beta linkage, is hydrolyzed in the small intestine by a specific disaccharidase called lactase, which is located in the brush border of the microvillus membrane. Lactase is detectable from the third month of human gestation and by 35 to 38 weeks gestation reaches 70% of the activity found in term newborns.3 This rate of development is markedly slower than that of the alpha glycosidases, sucrase, maltase, and isomaltase, which achieve activities comparable to those of term infants by 10 weeks gestation, and adult levels of activity by the 28th week. Clinically significant hypolactasia or deficiency of enzyme activity might thus regularly be expected in prematurely born neonates. Incomplete absorption of lactose has indeed been demonstrated in these infants, with appreciable residues of reducing substances in their stools when they are fed breast milk or modified cow milk formulas. It is interesting, however, that such babies do not generally develop clinically significant diarrhea and do in fact regularly pass relatively sparse and firm stools. Similarly, although incomplete absorption of lactose may occur in term neonates during the first weeks of life, there is frequently an absence of associated clinical signs or symptoms and such infants usually have entirely normal growth curves. This picture may obtain despite biochemical evidence of lactose malabsorption which may persist for up to 6 months after birth.
Lactase activity diminishes markedly shortly following weaning in all mammalian species other than man. In humans a less dramatic reduction in activity of this enzyme also occurs, beginning from age VA to 3 in Orientals and Blacks, and from age 5 among Caucasian children. Decreased biosynthesis of lactase in the post-weaning state is evidenced by a reduction both in enzyme activity and in immunologically detectable lactase protein. This condition is usually referred to as adult type of lactase deficiency and it appears to be inherited via a single autosomal recessive gene. An exception to this pattern of late onset lactase deficiency exists in certain populations which have practiced domestication of milk-producing animals and dairy farming for a sufficient length of time (estimated at 400 generations) to allow for a mutational adaptation which permits preservation of lactase activity. Maintenance of lactose tolerance among these milk drinking peoples is thought to be on a genetic basis, rather than as a result of individual adaptation to prolonged lactose ingestion. This conclusion is strengthened by animal and human studies which confirm that continued lactose intake fails to prevent the decline or to induce enzyme activity among individuals who normally experience the adult type deficiency. 5 A bimodal distribution has emerged in which the prevalence of lactose malabsorption exceeds 90% among adult native Americans, Orientals in the US, and certain African groups. Eighty-three percent of American Blacks are deficient for the enzyme in contrast to 24% of the white population (Figure).
Figure Prevalence of lactase insufficiency by racial group.
Congenital lactase deficiency is very rare. This condition is usually characterized by onset of vomiting, profuse diarrhea and malnutrition beginning with initial exposure to lactose in the first days of life, and persistent absence of lactase activity throughout life. Most infants described with this condition have total alactasia, inherited as an autosomal recessive disorder.6 Following elimination of lactose from the diet, they usually grow normally.
Although the activity of each of the disaccharidases may secondarily be depressed following extensive mucosal damage, lactase appears to be the most vulnerable since it is located very superficially among the brush border enzymes and its titers of activity are normally the lowest. The degree of lactase deficiency in these instances is generally directly related to the severity of damage to the villus membrane. Secondary lactase insufficiency may be associated with a variety of conditions but it most frequently follows acute gastroenteritis (Table 1). Significant depressions may follow clinically mild disease. Return of normal lactase activity depends on resolution of the underlying disorder, but it may lag behind clinical and mucosal histologic recovery by up to 4 months. Occasionally, infants may progress to develop acquired monosaccharide intolerance and mucosal atrophy, with consequent persistence of more chronic diarrhea and protein calorie malnutrition.8
The frequency of severe rotavirus induced gastrointestinal illness among infants may actually be related to a specific affinity of this virus for lactase, which may serve as the receptor site during the infections.9 Accordingly, it is hypothesized that the duration of rotavirus infection is limited by the replacement of desquamated, mature, lactase containing villus cells by more immature, lactase deficient cells.
In summary, lactase deficiency may present as total absence of the enzyme in the newborn, or as a diminution in activity from previously normal values presenting later in life. This pattern of acquired deficiency is subdivided into two types. The vast majority are genetically predisposed individuals in whom gradual decline of activity sets in sometime beyond the weanling period. In a second group the fall in enzyme activity is associated with damage to villus architecture and may occur at any point in the lifespan from birth to senescence as a result of exposure to the appropriate noxious agent. This type of hypolactasia usually occurs rather acutely and the process is often reversible with return of normal villus architecture.
With impaired digestion of lactose, unabsorbed carbohydrate remaining in the intestinal lumen represents an osmotic load which causes transmucosal fluid and electrolyte shifts into the lumen. Bacterial fermentation of unabsorbed carbohydrate results in its being split to smaller molecules with consequent increase in osmolality and in the elaboration of large quantities of lactic acid and hydrogen. This increase in intraluminal fluid and electrolyte content stimulates intestinal motility and shortens intestinal transit time. Thus, patients with the full blown picture of lactose intolerance may be expected to experience abdominal bloating, cramping, diarrheal stools of high acidic content (pH<5.5) nausea, vomiting, and flatulence.
CAUSES OF SECONDARY LACTASE DEFICIENCY
MECHANISM OF DIARRHEA WITH ALACTASIA
One might expect that the severity of symptoms should be directly linked only to the dose of ingested lactose and to the lactase activity of the intestine, with no other factors involved. The situation in such an idealized biologic system is illustrated in Table 2.
As shown in the upper left hand portion of the table, the molecular weight of lactose and its concentration in milk bear such a relationship to each other that roughly 100 mosm of lactose are found in a liter or quart of cow milk.
The upper right portion of the table is a bit more difficult to interpret. Stool osmotic activity results from presence of dissolved electrolytes, organic solids, proteins, peptides, carbohydrates, certain fatty food residues, etc. The water of a normally formed stool usually contains between 200 to 250 mosm/l from these sources. The increased water in diarrhea is associated with failure of reabsorption of sodium and other substances which tends to elevate stool osmolalities. Extensive losses from mucosal desquamation and exuded osmotically active materials such as protein may additionally increase osmolality, which in severe diarrheal diseases may reach values of the order of 300 to 350 mosm/l. For the purpose of illustration, a generous estimate has been made for the maximum stool osmolality of a normal 5-year-old in Table 2. About 100 ml of stool water of osmolality comparable to that of extraordinarily concentrated serum (about 350 mosm/l) are postulated to be excreted in a typical day. The total osmolar activity from all sources would thus be about 35 mosm each day.
The bottom portion of the table illustrates a possible scenario following the ingestion of cow milk by an individual with total alactasia. A 6 oz. glass of milk would yield 20 mosm of lactose to the lower bowel. Since this would all be traveling as a single bolus it would within a brief period introduce an osmolar load in excess of 50% of that which might normally gradually arrive in the colon of our hypothetical child over the course of an entire day. This should induce considerable bloating and distension and would probably be sufficient to result in a purgative action. Furthermore, colonic bacterial activity would tend to split the disaccharide into multiple smaller fractions which would increase this osmotic load. The ultimate conversion of each 12 carbon disaccharide into 6 molecules of 2 carbons each could very rapidly result in the elaboration of 120 mosm, which would unquestionably lead to explosive diarrhea. This was the principal symptomatology initially described by Holzel.2
The theoretical illustration requires modification for in vivo situations. Individuals with total alactasia are rare, while infants recovering from acute bouts of rotavirus diarrhea or with more chronic types of villus mucosal damage display significant hypolactasia, but not a total absence of activity as in the situation depicted in Table 2. Ingestion of small amounts of lactose in such patients might or might not result in bloating and distension. If milk ingestion would cause bloating in these instances, the osmotic activity generated might not be of sufficient force to result in a purgelike passage of stool; the resultant distension might then persist unrelieved. Patients with an inherent tendency to constipation and to rectosigmoid spasticity would be especially likely to suffer such discomfort without the relief of a bowel movement. Conversely, diarrhea might be regularly apparent in patients with hypolactasia if larger doses of lactose than would be equivalent to that in the 6 oz. of milk used in the illustration were taken, or if the milk contained more than the content of lactose in unmodified cow milk. These larger lactose concentrations are encountered in human milk and in cow milk formulas made to simulate human milk.
Furthermore, the foregoing calculations are based on rounded approximations, presuppose strict adherence to theoretical and stoichiometric concepts for the activity of osmotically functioning elements, and assume precisely measured lactose concentrations and lactase activities. The observed in vivo and clinical experience has not always exhibited such predictable qualities and the relationships between lactase deficiency and the clinical signs and symptoms of lactose intolerance do not always follow a straightforward relationship. Some of the factors which make for this unpredictability remain unclear. Variations in gastric emptying time, in intestinal motility and in normal bowel routines, differences in colonic flora and individual variations in response to bloating and abdominal pain, may all play some role in the variability of clinical manifestations reported.
Clearly, the extent and duration of small bowel mucosal injury, the persistence of infectious agents, and the degree of nutritional compromise are all involved in the severity of diarrhea following gastroenteritis. Continued administration of lactose in such situations may prolong diarrheal illness.
Lifschitz and colleagues demonstrated that when cow milk formulas were given following a bout of gastroenteritis the persistence and severity of diarrhea was directly related to the degree of lactose intolerance. ,0 The deleterious effects of continued lactose ingestion in such cases may be the result of increased stool water, electrolyte, and bicarbonate losses. In addition, the loss of metabolizable carbohydrate in the form of malabsorbed lactose may result in significant caloric deficits. Some investigators have demonstrated increased fat and nitrogen content in stools of infants with lactose intolerance, suggesting that lactose ingestion in these cases may impair absorption of other nutrients. Balance studies in adults, however, have failed to confirm increased nitrogen losses among lactose malabsorbers.11
In a blind feeding trial, lactose intolerant infants fed a hydrolyzed formula gained 70% more weight than those fed cow milk.12 These data suggest that infants with lactose malabsorption may develop progressive malnutrition, particularly following acute gastroenteritis. Such infants are at risk of developing pro* gressive disease characterized by intractable diarrhea and acquired monosaccharide intolerance. This syndrome, which generally occurs in infants less than 3 months old, is characterized by repeated bouts of progressively worsening diarrhea. Such infants may present with significant deficits in body weight, metabolic acidosis, and intolerance to dilute glucose feedings. These infants often have a history of multiple attempts at "therapeutic" fasting in order to control their diarrhea. Clearly, lactose intolerance alone is insufficient to explain the severity of symptoms in this syndrome. Prolonged protein calorie malnutrition, persistent gastrointestinal infection, bacterial overgrowth of the small bowel, and immunological factors may all play a role. Abnormal small bowel histology, with mucosal villous atrophy is frequently seen. These infants require prolonged hospitalization, parenteral nutrition and careful reintroduction of carbohydrates following nutritional restitution. Obviously, most infants with acute gastroenteritis and lactose intolerance do not develop the severe signs and symptoms noted above, even when lactose containing formulas are continued.13 This illustrates again the diversity of response to lactose ingestion, but highlights the importance of careful monitoring of infants and elimination of lactose when warranted.
Studies in older well children to assess symptomatology of abdominal pain, diarrhea, bloating and vomiting following'standardized lactose loads have yielded mixed results, suggesting that there is a wide range of tolerance of symptoms among patients with lactose malabsorption. No correlation was observed in one study between the symptoms in lactose malabsorbers vs. those who absorbed lactose following ingestion of 8 oz. milk.14 In this study population of 4- to 9-yearold black children, no clinical signs of lactose intolerance were demonstrated following ingestion of 8 oz. of milk, and the ad libitum daily milk intakes did not vary between those who were normal lactose absorbers and those who malabsorbed lactose. Others have conversely reported significantly greater daily milk intakes by children and families with normal intestinal lactase activities. 15 Clinical symptoms of lactose intolerance are reported in up to 28% of black teenagers. 16 One study suggests that patients tolerant of single doses as high as 8 oz. of milk may manifest symptoms with higher loads such as 16 oz. of milk ingested at one sitting.14 The suggestion that lactose intolerance may frequently account for chronic recurrent abdominal pain among children in whom hypolactasia or clinical evidence of lactose malabsorption may be demonstrated, is not borne out by crossover elimination diets and long-term elimination studies.17,18
Lactose intolerance may be suspected on clinical grounds, eg, in the adolescent with suggestive chronic symptomatology. Findings of acid stools which contain greater than 0. 5 mg% reducing substances as measured by Clinitest and large quantities of lactic acid strongly suggest carbohydrate malabsorption. The specific diagnosis of lactose malabsorption may be confirmed by lactose tolerance testing with sampling of blood glucose at 0, 15, 30, 60, 90 and 120 minutes, or by breath hydrogen analysis following feedings of a standard lactose load. A normal serum response should demonstrate a rise of at least 20 mg% in the glucose level or of 36 mg% in total reducing substances. An abnormal test response consists of a flat serum glucose absorption curve and clinical manifestations of malabsorption with symptoms of bloating, nausea, vomiting and/or diarrhea with acid stool which contains reducing substances. The finding of an abnormal lactose tolerance test should theoretically warrant subsequent performance of a glucose tolerance test to rule out the possibility that the results may be explained by a primary glucose-galactose malabsorption problem. However, the infrequent occurrence of the latter condition renders it unnecessary regularly to do the glucose tolerance test. The oral lactose tolerance test may yield about 25% false negative and about 5% false positive results. Diabetic subjects with lactose intolerance may possibly respond with false negative tests. Lactose is normally administered in a dose of 2 g/kg up to a maximum of 50 g as a 10% solution. The 50 g load is somewhat excessive in terms of normal dietary intake and is more than that which would be present in a quart of cow milk. Attempts to reduce the volume of the load in smaller youngsters by feeding higher concentrations than in 10% solutions often result in delayed emptying of the stomach and yield false positive tests in many instances.
Breath hydrogen analysis provides a simple, noninvasive technique for determining the presence of lactose malabsorption. We usually perform this study simultaneously with serum glucose determinations following ingestion of the standard lactose test dose in our laboratory. The test is based on the fact that hydrogen is produced as the colonic bacteria enzymatically degrade unabsorbed carbohydrate and a fixed proportion of this generated hydrogen is absorbed by the colonic mucosa, enters the bloodstream, and is excreted by the lungs. Endexpiratory breath may be sampled at fixed intervals by means of a mask or nasal prong device. A rise in hydrogen excretion of greater than 10 parts per million is considered consistent with lactose malabsorption. Breath hydrogen testing provides a useful noninvasive method for repeated monitoring of the recovery of lactase activity following acute injury such as from gastroenteritis.
In view of the frequency with which lactose intolerance may be encountered, a common dilemma for the clinician is to determine which patients require formal evaluation. This decision must be based on clinical signs and symptoms, and the intensity of investigation must similarly be based on the severity of manifestations. Clearly, the infant who makes an uneventful recovery from acute gastroenteritis and who tolerates early reintroduction of lactose-containing preparations has no need of any testing. The infant who persists in having multiple loose, explosive stools in the recovery phase should be evaluated with Clinitest for reducing substances and stool pH. Several stool samples should be checked, since single determinations of stool pH may be misleading even in the face of severe lactose intolerance. Performance of a lactose tolerance test with or without breath hydrogen analysis should be avoided in this phase, since massive diarrhea, dehydration, and shock may ensue. The infant who progresses to develop monosaccharide intolerance deserves more careful investigation, including small bowel biopsy and assay of disaccharidase activities.
Though hypolactasia may occur in the setting of many disorders that result in small bowel mucosal damage (Table 1), we do not recommend "empirical" elimination diets as "trials" of lactose tolerance status. If specific symptoms warrant, appropriate investigations should be initiated. More than one lactose tolerance test may sometimes be appropriate to assess improvement and normalization of small bowel function following a severe insult, eg, prior to reinstituting cow milk products in the recovery phase of celiac disease, or following initiation of therapy in widespread Crohn's disease of the small bowel.
The appropriate management of lactose intolerance would appear in all instances simply to be a restriction or elimination of lactose from the diet. However, no uniform approach is applicable to all patients, especially in view of the variations in ages, symptomatology, and etiology of lactose intolerance. Even for children of a specific age group who suffer a fairly predictable and similar type of difficulty with lactose, variations in dietary habits and other medical and social factors may dictate individualization of management.
In the very rare infant with congenital lactase deficiency, complete avoidance of lactose is mandated. Since lactose stimulates the absorption of calcium as well as magnesium, zinc and possibly iron from the intestine, such infants should be monitored carefully for deficiency of these nutrients.19
Recommendations are made here for three distinct types of patients with acquired hypolactasia: 1) infants recovering from acute diarrhea, 2) children with chronic problems associated with mucosal damage and atrophy, and 3) older children and adolescents with genetically predetermined late onset hypolactasia.
1) It is often difficult to assess the presence of lactose intolerance during the convalescent phase of acute gastroenteritis. Continuation of lactose containing cow milk formulas may lead to perpetuation and worsening of the diarrhea, with possible eventual development of the transport defect which leads to monosaccharide intolerance. It has become increasingly popular in the past 10 to 15 years to retard the reintroduction of lactose (cow milk) containing formulas. On some services only soy bean or predigested cow milk formulas which do not contain lactose are routinely used for the first days or weeks of refeeding following recovery from acute diarrhea. Many other services employ relatively diluted cow milk preparations for the early refeeding and the first signs of continuing loose stools automatically are met, without any special studies, with a switch to a non-lactose containing diet.
Recent clinical trials have demonstrated that mild episodes of gastroenteritis treated with 24 hours of oral clear fluid hydration therapy may safely be followed with rapid reinstitution of full strength cow milk formulas, especially if the infants are more than 9 months of age.20 We have been especially pleased to see this validation of the form of treatment for such patients which we have continually advised in the past. We do not advocate prolonged or therapeutic fasting for acute diarrhea, since patients who are given adequate calories and protein have been shown to recover more rapidly from diarrheal illness and are at less risk of developing chronic intractable diarrhea and acquired monosaccharide intolerance.21 However, although cow milk formulas may safely be reinstituted in most cases, the practitioner must be prepared to follow the patient carefully. If diarrhea recurs, serial examinations of stool for pH and for presence of reducing substances may be indicated. Change to a lactose-free formula should be made if the stools are excessively acid and contain reducing substances, since this indicates that hypolactasia is present and lactose intolerance has developed.
2) Children with chronic diarrheal illness secondary to such disorders as celiac disease, short gut, ileitis, or following gastrectomy, may also require lactose restriction because of insufficient enzyme activity (Table 1). These patients should be tested and evaluated for hypolactasia and lactose intolerance. Other factors including altered intestinal motility, bacterial overgrowth of the small bowel, bile salt malabsorption, and inadequate lipase and peptidase activity may play a major role in the pathogenesis of diarrheal illness regardless of lactose intake. However, if they prove to be lactase insufficient, lactose ingestion in such patients may exacerbate diarrhea and should be restricted. In some cases, as in celiac sprue, lactose restriction is required only until resolution of the underlying lesion and restitution of normal enzyme activity is achieved. In other cases, as in short gut syndrome, long-term lactose restriction may be necessary.
3) Milk and lactose restriction in the older child or adolescent with adult onset lactose intolerance may be appropriate when the manifestations of clinical lactose intolerance are present. In view of the permanent restrictions which are necessary, it is advisable to confirm lactose intolerance by testing.
Although the lactose content of certain dairy products is diminished by processing, many commonly "acceptable" dairy products contain relatively high lactose concentrations, eg, commercial yogurt often contains as much as 9 g/8 oz in comparison to milk, which contains 12 g/8 oz. Processed cheeses have the lowest levels of lactose. Patients with severe intolerance must screen their diets very carefully, since lactose is found in many "non-dairy" foods. When intake of meats and legumes is poor, careful attention must be paid to the adequacy of calcium intake. In such cases, calcium supplementation should be provided to maintain adequate calcium intake (800 mg/day among toddlers and children, 1,200 mg/day among adolescents).
Recently, a commercial preparation of lactase derived from a fungus (Lact-Aid) has been introduced. Incubation of a quart of milk with a few drops of the preparation may reduce the lactose content by from 70% to 100%, depending on the number of drops used and the time over which incubation is permitted before the milk is utilized. The resultant milk is sweeter because of the elaboration of glucose, but is welltolerated. Some commercial dairies have begun to feature cottage cheese and other products which have been pretreated with this vegetable source enzyme and they advertise the products as "lactose reduced. "
A major problem for the adolescent and young adult with hypolactasia is that he or she is often offered lactose-containing products at restaurants and in homes of others, in social situations in which it is impossible to pretreat the food or drink with enzyme products. Each subject must leam the individual levels of tolerance and make decisions with respect to the precise amount of discomfort that will be tolerated to "pay the price of the goody. " Intolerant patients are often willing to go to considerable lengths to be part of the crowd. Although continued ingestion of lactose does not induce the enzyme, it also does not appear to cause any permanent harm in this group of patients. Individuals should be allowed therefore to set their own limits. The automatic complete restriction on dairy products which is so generally advised these days is in many instances too restrictive, especially for many patients in whom testing has not been performed and who may not even profit from lactose avoidance.
1. Jacobi A: Milk-sugar in infant feeding. Transactions of the American Pediatric Sacien I901;13:I50.
2. Holzel A, Schwartz V, Sutcliffe KW: Defective lactose absorption causing malnutrition in infancy. Lancet 1959; i:1126.
3. Antonowicz I, Lebenthal E: Developmental pattern of small intestinal enterokinase and disaccharidase activities in the human fetus. Gastroenterology 197?; 72:1299.
4. Auricchio S, Rubino A, Murset G: Intestinal glucosidase activities in the human fetus, embryo, and newborn. Pediatrics 1965; 35:944.
5. Cuatracasas PD, Lockwood DH, Caldwall JR: Lactase deficiency in the adult. Lancet 1965; i;14.
6. Savilahti E, Launiala K, Kuitunen P: Congenital lactase deficiency. Arch Du Child 1983:58:246.
7. Boyle JT, Celano P, Koldovsky O: Demonstration of a difference in expression of maximal lactase and sucrase activity along the villus in the adult rat jejunum. Gastroenterology 1980;79:503.
8. Lifshitz F1 Coelio-Ramirez P, Guttierez-Topete G: Monosaccharide intolerance and hypoglycemia in infants with diarrhea. J Pediatr 1970; 77:595.
9. Holmes IH, Rodger, SM, Schnagl RD. et al: Is lactase the receptor and uncoating enzyme for infantile enteritis (rota) viruses.' Lancet 1976; i; 1 387.
10. Lifshitz F, Coelio-Ramirez P, Guttierez-Topete G, et al: Carbohydrate intolerance in infant* with diarrhea. J ftdiarr 1971:79:760.
11 . Calloway DH, Chenoworth WL: Utilization of nutrients in milk and wheat based diets by men with adequate and reduced abilities to absorb lactose. Am ) Clin Nuir 1973; 26:939.
12. Mitchell JD, Brand J, Halbisch J: Weight gain inhibition by lactose in Australian Aboriginal children. Lancet 1977; i:500.
13. Torun B, Solomons NW, Viteri FE: Lactose malabsorption and lactose intolerance: implications for general milk consumption. Archi«! Larm American Nutrition 1979; 29:445.
14. Garza C, Scrimshaw NS: Relationship of lactose intolerance to milk intolerance in young children. AmJ Clin Nutr 1976; 29:192.
15. Lebenthal E, Antonowicz I, Schwachman H: Correlation of lactase activity, lactose intolerance and milk consumption in different age groups. Am J Clin Nutr 1976; 28:595.
16. Mitchell KJ, Bayless TM, Palge DM, el ah Intolerance of eight ounces of milk in healthy lactose intolerant teenagers, Pediatrics 1975; 56:718.
17. Barr RG, Becker MC, Levine MD, et al: Recurrent abdominal pain of childhood due to lactose intolerance: A prospective study. N Engl I Med 1979; 300:1449.
18. Lehenthal E, Rossi TM, Nord KS, et al: Recurrent abdominal pain and lactose absorption in children, ftthemcs 1981; 67:828.
19. Ziegler EE, Fomon SJ: Lactose enhances mineral absorption in infancy, J Mian Gastroenterol Nufr 1983; 2:288.
20. Placrek M, Walker-Smith JA: Comparison of two feeding regimens following acute gastroenteritis in infancy. J Pediarr Geitroenterof Nun 1984; 3:245.
21 . Chung AW, Viscorova B: The effect of early oral feeding versus early oral starvation on the course of infantile diarrhea. J ftdiotr 1948; 33: 14.
CAUSES OF SECONDARY LACTASE DEFICIENCY
MECHANISM OF DIARRHEA WITH ALACTASIA