Lactase deficiency in Indians

Transcription

1 editor: Robert B. Bradfield, Ph.D. international nutrition Lactase deficiency in Indians Vinodini Reddy, M.D., D.C.H., and Jitender Pershad, M.B.B.S., D.C.H., M.Sc. In recent years, great interest has arisen in the incidence of lactose intolerance in apparently healthy subjects. This disorder has been reported to be common among Asians, and African and American Negroes, in contrast to a low prevalence in Caucasians. Most of the subjects who have been studied are Negroes and Oriental adults, residing in the United States (1) and Australia (2), and the lactose intolerance in these subjects has been attributed to an inherited lactase deficiency. In view of these observations, it has been suggested that the importance of milk in planning diets for undernourished populations in Asian countries should be re-evaluated (1) and that supplementation of skim milk may not be an efficient method to combat protein malnutrition (2). The results of a recent study reported from India have also shown that lactose intolerance is frequently seen among adult subjects (3). There is, however, little information regarding its incidence in children. As preschool children are the major beneficiaries of many nutrition programs utilizing skim milk as a supplementary food, this question acquires considerable practical importance. Also to be examined is whether lactose intolerance necessarily implies an intolerance of milk. An investigation was therefore undertaken to determine the incidence of lactose intolerance and the levels of intestinal lactase in a group of Indian adults and children. Materials and methods Peroral intestinal biopsies were done in 12 apparently normal adults. The biopsies were performed with a Crosby capsule and all specimens were obtained from the upper part of the jejunum under direct fluoroscopic vision. The biopsy specimen was divided into two portions: one portion was placed in formalin for histological examination and the second was placed in an ice-cold normal saline solution. The sample was weighed after removing the excess saline and was homogenized with distilled water. The enzymes, i.e., lactase, sucrase, and maltase, were measured by the method of Dahlqvist (4) and protein was determined by Lowry s method (5). Oral lactose tolerance tests were done in 18 normal adults including the 12 subjects in whom the biopsies were also performed. Their ages ranged from 20 to 40 years and none of them was in the habit of drinking milk. A loading dose of 50 g of lactose in 400 ml of water was given after an overnight fast. Finger-prick blood samples were obtained at 0, 30, 60, and 120 mm after administration of the dose. Blood sugar levels were determined by Park and Johnson s method (6). The subjects were observed for symptoms of intolerance such as abdominal pain, distension, or diarrhea, during the next 24 hr. A few days later, the test was repeated using a glucose (25 g) and galactose (25 g) mixture. In six of these subjects, 60 g of dry skim milk containing 30 g of lactose, reconstituted to fluid milk, was given daily and the biopsies repeated after 4 weeks. Studies in children Jejunal biopsy was performed in 15 normal children using a pediatric Crosby capsule. The biopsy specimens were utilized for histological examination and disaccharidase assay, as described for adults. Oral lactose tolerance tests were done in 54 apparently normal children including the 15 subjects in whom biopsies were also performed. Their ages ranged from 7 months to 7 years. Children Studies in adults From the National Institute of Nutrition, Indian Council of Medical Research, Jamai Osmania, Hyderabad-7 (A.P.), India. The America,z Journal of clinical Nutrition 25: JANUARY 1972, pp Printed in U.S.A.

2 LACTASE DEFICIENCY IN INDIANS 115 below 3 years were getting either breast milk or cow s milk, whereas the older children did not get milk regularly. There was no history of milk intolerance in any of these subjects. A lactose load of 2 g/kg body wt was used. In eight children who showed intolerance, the study was repeated with a lower dose of 1 g lactose/kg. All these children were given supplements of reconstituted dry skim milk in quantities, which provided 2 g lactose/kg as a single dose once a day for the next few days and they were observed for symptoms of lactose intolerance. In six cbildren with lactose intolerance, intestinal motility was studied under fluoroscopy after giving them barium mixed with lactose. Barium mixed with skim milk containing an equivalent amount of lactose was administered a few days later. Results Studies in adults Gross appearance. Under the dissecting microscope, the mucosal surface showed either leaf-like villi or a convoluted pattern; no case showed finger-like villi. Histology. The mucosal pattern was essentially normal with long and slender villi in most cases and broad leaf-like villi in a few other cases. Disaccharidases. Lactase activity in the intestinal mucosa was low in all the subjects studied, whereas the activity of the other two enzymes, sucrase and maltase, was normal. The values ranged from 0 to 0.9, 2.0 to 7.6, and 5.4 to 33.7 units (U)/g wet wt for lactase, sucrase, and maltase, respectively. The values expressed per gram of protein also indicated isolated lactase deficiency (Table 1). In six subjects, in whom the biopsies were repeated 4 weeks after skim milk supplementation, there was no change in lactase activity, but there was a significant increase in protein concentration of the mucosa (Table 2). All the six subjects had milk intolerance initially but there were fewer symptoms at the end of 4 weeks. Lactose tolerance lest. Nine out of eighteen subjects studied developed symptoms of intolerance after the lactose load. They complained of abdominal pain, distension, and passed loose stools within 24 hr. Eleven subjects showed flat tolerance curves as judged by a failure of blood sugar to rise above 25 mg/100 ml from basal. The mean maximum rise in blood sugar was 33 mg/loo ml in the tolerant group and 1 9 mg/loo ml in the intolerant group. However, not all of the latter subjects had flat curves. Two subjects had intolerance but showed a normal rise in blood sugar and four had flat curves but no symptoms (Table 3). Glucose-galactose tolerance curves were normal in all the subjects, the rise in blood sugar being more than 25 mg/100 ml. Studies in children Gross appearance of the intestinal mucosa showed a leaf-like or convoluted pattern similar to that observed in adults. Histology. Mucosal pattern appeared to be normal. Disaccharidases. Lactase activity ranged from 0.2 to 6.6 U/g wet wt (Table 1). The enzyme concentration was more than 1 U/g TABLE I Levels of intestinal disaccharidases Lactase Sucrase Maltase Subjects No. Unit/g wet weight Unit!g protein Unit/g wt wet Unitlg protein Unit/g svet wt Unit/g protein Adults (0-0.9) 7.8 (2-24) 3.8 (2-7.6) 97 (31-213) 14.5 ( ) 323 ( ) Children over years Children below 3 9 ( ) 2.1 ( ) 54 ( ) 4.2 (56-236) 88.4 ( ) 10.8 ( ) 249 years ( ) (21-169) ( ) (47-137) (5-19.2) ( ) Normals (18). a Mean with range. Unit of disaccharidase activity = micromoles disaccharide hydrolyzed/minute

3 116 REDDY AND PERSHAD TABLE 2 Effect of skim milk supplements on intestinal lactase levels Initial Subject Lactase Intestinal unit/g wetwt protein, mg/g Mean TABLE 3 Lactose tolerance test su- t jec #{176} S Adults Tolerant 9 Intolerantb 9 Total 18 Children Tolerant 34 Intolerantb 20 Total 54 Maximum in blood mg/loo After 4 weeks of milk Lactase unit/g wetwt Intestinal protein, mg/g rise sugar, ml 33 (22-49) 19 (8-36) 36 (10-70) 26 (3-43) No. of subjects with flat curves a Rise in blood sugar was less than 25 mg/loo ml. b On the basis of symptoms in all the nine children who were below 3 years, whereas the levels ranged from 0.2 to 1.4 U/g in the older children. The levels of sucrase and maltase were in the normal range in all children. Lactose tolerance test. Twenty of the fiftyfour children developed symptoms of intolerance following the lactose load of 2 g/kg (Table 3). None of the eight in whom the test was done with a dose of 1 g/kg had such symptoms but they did show a satisfactory rise in blood sugar, which did not vary with the dose. Twenty-two children showed flat tolerance curves. The elevation in blood sugar was less than 25 mg/100 ml in 11 out of 34 tolerant and 11 out of 20 intolerant children. There was no correlation between the rise in blood sugar, symptoms of intolerance, and the enzyme activity. After administration of reconstituted dry skim milk, only four children exhibited symptoms. Even in these subjects, the symptoms disappeared when the same amount of milk was given in two divided doses. Barium meal studies. In two of the six children studied, intestinal motility was found to be normal when the barium was given either with skim milk or with lactose. In the other four subjects it was normal with skim milk but rapid intestinal movement was observed when lactose was given, the barium reaching the cecum within an hour. Discussion The results of the present study confirm that the incidence of lactase deficiency and lactose intolerance is high among Indian adults. Lactase activity was less than 1 U/g wet wt in all the adult subjects, whereas the levels of sucrase and maltase were normal. The cause of this isolated lactase deficiency in adults is still not known. Etiologic possibiities that have been considered include an adaptation to decreased milk intake, an acquired deficiency as a result of mucosal injury, and an inherited trait with delayed clinical expression. Under the dissecting microscope, the mucosa showed either leaf-like villi or a convoluted pattern, but there were no finger-like villi as described in healthy Western subjects. These changes have been reported to be cornmon to people living in the tropics and some researchers have suggested that these changes may be acquired by recurrent exposure to parasitic and bacterial invasion (7). However, the histological pattern was essentially normal in the subjects. The villi were long and slender except in a few cases in whom short leaf-like villi were observed. There was no evidence of mucosal damage that could account for the enzyme deficiency. The adult subjects and the children over 3 years of age were not accustomed to drinking milk, whereas the infants were receiving either breast milk or cow s milk and their lactase activity was normal. Association of

4 LACTASE DEFICIENCY IN INDIANS 117 lactase deficiency with a history of low milk consumption has been pointed out earlier (8); there may be an adaptive decline in the enzyme following withdrawal of milk from the diet after weaning. A post-weaning decrease in lactase activity has been demonstrated in animals and it has also been shown that this decrease can be prevented if lactose is provided as the only source of carbohydrate (9). However, milk drinking does not seem to affect lactase levels in man. Recently, five normal healthy adults, who were in the habit of drinking substantial amounts of milk regularly, were also investigated. Lactase activity was found to be less than 1 U/g wet wt in all of them, in spite of regular milk intake. In the six subjects in whom biopsies were repeated (4 weeks after skim milk supplementation), there was no increase in lactase activity. Similar attempts to raise the enzyme level with a prolonged lactose diet have failed (10, 1 1). Conversely, lactose deprivation in normal subjects (1 2) or as in the treatment of galactosemia (1 3) does not lower lactase levels. These observations argue against adaptation to lack of substrate playing a role in low lactase levels. All the subjects who received skim milk supplements showed intolerance initially but the symptoms became milder or disappeared altogether after 3 to 4 weeks, though there was no increase in the enzyme activity. Cuatrecasas et a!. (10) have also observed that absorption can improve with prolonged intake of lactose; however, the exact mechanism of this adaptation is not clear. Lactase levels were found to be higher in children than in adults. All the nine children under 3 years of age had lactase activity above 1 U/g wet wt, whereas in older children the values ranged from 0.2 to 1.4 U/g, and in adults, eight out of twelve subjects had levels less than 0.2 U/g. These observations suggest that lactase activity decreases with advancing age. Lactose tolerance tests in Negroes showed a decrease in the tolerance to lactose load with increasing age, presumably due to lactase deficiency (14). Normal levels of lactase were found in newborns in Baganda where lactose intolerance is common among adults (15). Lactase deficiency is probably a genetically determined defect, which becomes overt later in life. Lactose tolerance test is considered to be a useful screening procedure for evaluating the clinical problem of milk intolerance. The development of symptoms like cramps or loose stools and a flat curve, i.e., a rise in blood sugar of less than 25 mg are taken as indicative of lactase deficiency (16). In the present study, no correlation was observed between the symptoms of intolerance, rise in blood sugar following lactose load, and the intestinal lactase levels. The enzyme activity was less than 1 U/g wet wt in all the adult subjects but only 50% of them had lactose intolerance. Similarly, in children it was observed that all those who showed symptoms of intolerance had lactase deficiency but the converse was not true. Some children showed a satisfactory rise in blood sugar and exhibited no symptoms following lactose load, although their lactase activity was low. Sheehy and Anderson (17) have also reported that some healthy persons with low lactase levels did not manifest intolerance to lactose. On the other hand, Dunphy et al. (1 8) found normal lactase activity in some lactose intolerant subjects. The possible explanation for this discrepancy could be that the enzyme levels determined in a single biopsy specimen may not indicate the total lactase available. Desai et al. (1 9) have found that in patients with tropical sprue, as well as in normal subjects, lactase activity in the ileal mucosa was much higher than that observed in jejunal mucosa. In patients recovering from celiac disease, tolerance to milk improves, lactose tolerance test becomes normal, but their lactase levels remain low for years (20). These observations raise an important question. Does lactase deficiency or intolerance to lactose load indicate clinical milk intolerance? Several factors like the total lactase available, the dose of lactose, and the amount of milk consumed at a time are important in determining symptomatic response. Both our studies and those reported by others (10) reveal that some lactose-intolerant subjects can consume as much as one quart of milk daily if they drink it in small amounts throughout the day.

5 118 REDDY AND PERSHAD In the present study, symptoms of intolerance were observed in 20 children when 2 g/kg of lactose was given. In eight of these intolerant children, when the test was repeated with a dose of 1 g/kg, none of them manifested any symptoms and all showed a satisfactory rise in blood sugar as well. These observations suggest that although the enzyme activity is low, it may be adequate to digest the lactose when presented in small amounts. Out of 20 children who had intolerance to a 2-g/kg lactose load, only 4 showed symptoms when milk containing equivalent amounts of lactose was given. Even in these children, symptoms disappeared when the milk was given in divided dcses. All the children could consume 200 ml milk containing 1 5 g lactose at a time without any adverse effects. The speed of gastric emptying and the intestinal motility may influence the symptomatic response to lactose. In fact, this was confirmed by barium meal studies, which showed that unlike milk, ingestion of lactose resulted in rapid peristalsis. It is possible that protein and other constituents of milk may affect gastric emptying and intestinal motility, and this would suggest that lactose intolerance need not necessarily indicate milk intolerance. Skim milk is used extensively as a source of protein in the treatment of protein-calorie malnutrition. There are a few reports (21) indicating a high incidence of lactose malabsorption in children with protein-calorie malnutrition. However, there is a large body of evidence to show that these children are benefited by a skim milk diet (22). Diarrhea improves as the treatment is continued and there is an excellent clinical and biochemical response. These observations indicate that, low levels of lactase notwithstanding, the administered milk is absorbed and utilized. Many developing countries are currently receiving dry skim milk from various international organizations and this is being used as a protein supplement, particularly for preschool children. In most nutrition programs, the amount of milk given to a child at a time rarely exceeds 200 ml. Results of the nresent study indicate that the incidence of lactase deficiency and lactose intolerance is lower in children than in adults, and even those children who have lactose intolerance are unlikely to develop symptoms with these amounts of milk supplements. High incidence of lactase deficiency should not, therefore, be used as an argument against the distribution of skim milk to undernourished populations in Asian countries. Summary Intestinal biopsies, disaccharidase assays, and lactose tolerance tests were performed on Indian adults and children of different ages. The results showed an isolated lactase deficiency in all the adult subjects and lactose intolerance in 50% of them. Skim milk supplementation for 4 weeks had no effect on lactase activity. The incidence of lactase deficiency and lactose intolerance was lower in children. Twenty out of fifty-four children were intolerant to a lactose load of 2 g/kg but none of the eight retested with 1 g/kg had symptoms. Only 4 out of 20 intolerant children had symptoms when milk containing an equivalent amount of lactose was given and even in these children symptoms disappeared when the milk was given in divided doses. The results of these studies clearly show that lactose intolerance does not necessarily imply milk intolerance. The incidence of lactose intolerance and low levels of lactase activity therefore are not reliable guides to assess milk tolerance and the use of skim milk to improve the dietaries of poorer sections of the population should not be based on these considerations. We are grateful to Dr. C. Gopalan, Director, and Dr. S. G. Srikantia, Deputy Director, for their keen interest and valuable suggestions during the study. We also thank Dr. D. Krishnamurthi, for his help with the histological studies. References 1. HUANG, S. S., AND T. M. BAYLESS. Milk and lactose intolerance in healthy Orientals. Science 160: 83, DAVIS, A. E., AND T. B0LIN. Lactose intolerance in Asians. Nature 216: 1244, DESAI, H. G., A. V. CHITRE AND K. N. JEE- JEEBHOY. Lactose loading-a simple test for

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