Intestinal Lactase Deficiency in Ceylon (Sri Lanka)

Intestinal Lactase Deficiency in Ceylon (Sri Lanka)

72:1257-1259, 1977 Copyright © 1977 by the American Gastroenterological Association Vol. 72, No.6 GASTROENTEROLOGY Printed in U.SA. INTESTINAL LAC...

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72:1257-1259, 1977 Copyright © 1977 by the American Gastroenterological Association

Vol. 72, No.6

GASTROENTEROLOGY

Printed in U.SA.

INTESTINAL LACTASE DEFICIENCY IN CEYLON (SRI LANKA) BRIAN SENEWIRATNE, M.A. (Cantab), M.B., B.CIR.(Cantab), M.D. (Lond), F.R.C.P., SHANTHI THAMBIPILLAI, M.B., B.S. (Ceylon), AND HERMIN PERERA Clinical Research Unit, Department of Medicine, University of Ceylon, Peradeniya, Ceylon

Lactose tolerance tests (LTT) in 200 normal adult Ceylonese have shown that 145 (72.5%) had a flat LTT, indicating a population prevalence oflactase deficiency of66.2 to 78.8%. Jejunal lactase estimations in a smaller sample (41) confirmed this. Twelve of 55 subjects (21.8%) with a normal LTT had intestinal symptoms after lactose and intestinal lactase was low in most of them. It is suggested that little lactase is required to elevate the blood sugar but that more may be required to prevent diarrhea. On the other hand, 65.5% had no symptoms despite a flat LIT, and the possible reasons for this are considered. Isolated lactase deficiency (ILD) is common in the non-Caucasian races such as blacks (both African l and American2-4), the Asians (Indians, 5 Chinese6 and Thais7,8) and the Australian aborigines,9 exceptions being certain milk-drinking Pakistanis lO and Africans. I It is also probably common among the Greeks,11 Filipinos,12 New Guineans,13 and South American Indians,I4 although the numbers of normal subjects studied have been small. Caucasians (white Americans,15 white Australians,I6 Danish,I7 Finnish,I8 and the Britishl9 ) who consume more milk than the non-Caucasians, have a low incidence of ILD. The per capita milk intake in Ceylon is 10w6,20 and Bolin et aI., 6 who think that lactase deficiency is a consequence of a low milk intake, predicted that these people would have a high incidence of ILD. There has been no study of lactase deficiency in Ceylon.

Patients and Methods Lactose tolerance tests (LTT) were done in 200 (177 female and 23 male) patients aged 16 to 78 years who presented with trivial nongastrointestinal complaints such as coryza, headache, and nonspecific chest pain. Those who presented with gastrointestinal symptoms were excluded. This could underestimate the prevalence of ILD in the population as those who might have had symptoms attributable to milk intolerance have been excluded. However, the error is likely to be small because it was found (to be published) that despite a high incidence of ILD, it is a rare cause of abdominal symptoms in Ceylon, presumably because ofthe low consumption of milk. Lactose (50 g) in 300 ml of water was administered orally

after an overnight fast. The capillary blood sugar was determined21 before and at 20-min intervals for 100 min. Intestinal symptoms (diarrhea, abdominal pain, flatulence, and borborygmi) were frequently looked for over the next 24 hr. Subjects who had a flat LTT (blood sugar rise ofless than 20 mg per 200 ml) were given 25 g of glucose in 150 ml of water and the blood sugar was estimated as in the LTT. Galactose was not given as it is rapidly metabolized by the liver and fails to reach the peripheral circulation unless its metabolism in the liver is blocked by ethanol. 22 There is therefore no advantage in administering a mixture of glucose and galactose inasmuch as the resultant blood sugar response would be the same as when glucose alone is given, provided the comparable solutions are isosmotic. 6 Fourteen patients with a flat LTT were given 25 g of xylose in 450 ml of water and the xylose was estimated23 in urine collected over the next 5 hr. An oral sucrose tolerance test (50 g of sucrose in 300 ml of water) was done on another 23 subjects who had a flat LTT. Intestinal biopsies were done in 41 unselected subjects without knowledge of the results of the LTT using a Crosby capsule radiographically located about 5 cm beyond the ligament of Trietz. Biopsy specimens were immediately frozen and lactase was estimated24 within 24 hr.

Results LTT. Of the 200 subjects, 145 (72.5%) had a flat LT!'. The detailed results are shown in table 1. A rise of blood sugar >20 mg per 100 ml is considered normal by several workers,8, 15, 16, 18,25 although others11, 26 raise this to > 25 mg per 100 m1. A rise of between 20 and 25 mg per 100 ml could represent a borderline result. Of the 55 subjects who had a normal (>19 mg per 100 mD rise, 22 (40%) were in this boderline group. The mean maximum rise of the blood sugar in the 145 subjects with a flat LIT was 7.7 mg per 100 ml (SE 0.78) and in the 55 subjects who had a normal test, 32.5 mg per 100 ml (SE 1.71). Of the 55 subjects with a normal LTT, 12 (21.8%) had gastrointestinal symptoms; 13 of them had lactase estimations done and in 9 the lactase was less than 0.8 units per g wet weight mucosa (see below). In 145 subjects

Received July 16, 1976. Accepted December 3, 1976. Address requests for reprints to: Brian Senewiratne, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane 4102, Australia. Dr Senewiratne's present address is: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane 4102, Australia. The authors wish to thank the Nuffield Foundation, London, for a research grant to one of us (B. S.). They also wish to thank Hemamala Amunugama for her technical help and Mrs. Kamalini Senewiratne for checking the references. 1257

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with a flat LTT a surprisingly large number, 95 (65.5%) had no symptoms. The symptoms consisted mainly of diarrhea (1 to 4 liquid stools) occasionally associated with abdominal pain. In almost all (93.5%) symptoms occurred within 3 hr of the ingestion of lactose. In the rest, symptoms were delayed for 3 to 6 hr. No racial differences were found. There are two major races in Ceylon, the Sinhalese (71%) of Aryan origin who migrated down from North India some 2000 years ago, and the Tamils (20%) of Dravidian origin who came here from South India sometime later. There are no major dietary differences between the two groups. Of the 158, 116 (73.4%) Sinhalese and 22 of the 31 (71.0%) Tamilis had a flat LTT. The differences were not significant. Glucose, xylose and sucrose tests. The glucose tolerance test was normal in all ofthe subjects who had a flat LTT. The mean maximum rise in the blood sugar was 58.5 mg per 100 ml (range 27 to 108 mg per 100 mI). The xylose excretion test was also normal in all subjects. The 5-hr excretion after 25 g of xylose ranged from 4.0 to 7.2 g. Sucrose tolerance tests were normal in all 18 subjects with a flat LTT on whom this test was done. The mean rise of blood sugar was 62.7 mg per 100 ml (rar.ge 31 to 123 mg per 100 mI). I ntestinallactase deficiency. A frequency distribution polygon of the log lactase activity of 41 specimens of mucosa did not show a normal distribution. This was confirmed by a percentage cumulative frequency plot on probability paper. However, when lactase values between 0.0 and 0.8 unit per g wet weight mucosa were considered, the distribution was normal. This suggested that lactase values were bimodally distributed with a hypolactasia group between 0.0 and 0.8 unit per g wet weight mucosa and a normal group above this. Of the 41 subjects in whom intestinal lactase estimations were done, 35 (85.4%) had a low lactase (0.8 unit per g wet weight mucosa or less). This estimate had a standard error of 5.5%, indicating a population prevalence of lactase deficiency of 74.4 to 96.4%. A more detailed breakdown of the results is shown in table 2. In 41 subjects a LTT and an intestinal biopsy were done. Only in those with a normal LTT and an absence of symptoms after lactose was the intestinal lactase normal. In all others the lactase was abnormally low and this included those who had abdominal symptoms after lactose but a normal rise in blood sugar.

TABLE 2. Intestinal lactase estimations in 41 normal subjects Lactase units/g wet weight mucosa

No.

0-0.50 0.51-0.80 0.81-2.00 2.01-2.50

26 9 4 2

Total

41

%

63.4 } 85.3 21.9 9.8 4.9 100.0

Discussion Isolated lactase deficiency is common in Ceylon. Of 200 subjects, 72.5% (SE 3.2) had a flat LTT, indicating a population prevalence of 66.2 to 78.8%. Estimations of jejunal lactase in a smaller sample (41) supported this. Although estimations of other enzymes such as sucrase were not done, the normal absorption of glucose, xylose, and sucrose strongly suggests that this is a specific defect of lactose absorption rather than a generalized malabsorption state such as tropical sprue, which produces a secondary lactase deficiency. 5, 27 There was a poor correlation between symptoms and the rise in blood sugar after lactose. Of subjects who had a normal rise in the blood sugar, 21.8% had intestinal symptoms. It is possible that in these subjects the total available lactase, although sufficient to raise the blood sugar was insufficient to clear the intestinal lactose load and thus prevent diarrhea. Conversely, 65.5% of those with a flat LTT had no symptoms, a finding which has been observed by others. 19, 28 There are at least three possible explanations for this anomalous finding. First, the blood sugar concentration is determined by the opposing effects of two dynamic processes, the entry and exit of glucose from the circulation. Alterations in these rates, such as a slow entry of lactose into the intestine (e.g., pyloric stenosis) could result in clearing of the intestinal lactose load without a significant change in the blood sugar. Second, the intestine could have adapted to the presence of unabsorbed lactose. Third, consideration must be given to the unlikely but possible situation that lactose is being metabolized by some other pathway. Mucosal specimens with unmeasurable lactase activity are able to metabolize considerable quantitites of lactose. 29 It is possible that races who for generations have consumed little milk have developed some nonhydrolytic pathway which is known to occur in certain bacteria. 30, 31 The finding of a high prevalence of lactase deficiency TABLE 1. Maximum blood sugar rise after oral lactose in 200 subjects does not necessarily mean that such a deficiency is of Maximum blood % No. clinical importance. In England, lactase deficiency has sugar rise been claimed to be an important cause of a "functional" mgllOO ml diarrhea. 32 In countries which have a high prevalence of >25 33 16.5 lactase deficiency but a low intake of milk this might 25-20 22 11.0 well be different. Until an evaluation of the role of milk 28 14.0 19-15 in the functional diarrheas in these countries has been 14-10 34 17.0 72.5 made, it would be unwise to conclude that the etiologi9-5 45 22.5 5-0 21 10.5 cal basis of a chronic diarrhea in these countries is <0 17 8.5 lactase deficiency (despite the demonstration of such a deficiency) unless there is a complete remission of the Total 200 100.0 symptoms on the withdrawal of milk. Such a study is

LACTASE DEFICIENCY IN CEYLON

June 1977

now in progress. Preliminary results indicate that the danger in these countries is an overestimation of the clinical importance of this common enzyme deficiency and the risk of missing a serious intestinal lesion such as chronic intestinal amebiasis or a neoplasm of the bowel because of a mistaken diagnosis of a lactoseinduced diarrhea. The situation is obviously different when such subjects change their dietetic habits, such as when they migrate to another country. REFERENCES 1. Cook GC, Kajubi SK: Tribal incidence of lactase deficiency in Uganda. Lancet 1:725-730, 1966 2. Cuatrecasas P, Lockwood DH, Caldwell JR: Lactase deficiency in the adult. A common occurrence. Lancet 1:14-18, 1965 3. Bayless TM, Rosensweig NS: A racial difference in incidence of lactase deficiency. JAMA 197:968-972, 1966 4. Welsh JD: Isolated lactase deficiency in humans: report on 100 patients. Medicine 49:257-277, 1970 5. Desai HG, Chitre AV, Parekh DV, et al: Intestinal disaccharidases in tropical sprue. Gastroenterology 53:375-380, 1967 6. Bolin TD, Davis AE, Seah CS, et al: Lactose intolerance in Singapore. Gastroenterology 59:76-84, 1970 7. Keusch GT, Troncale FJ, Thavaramara B, et al: Lactase deficiency in Thailand: effect of prolonged lactose feeding. Am J Clin Nutr 22:638-641, 1969 8. Flatz G, Saengudom CH, Sanguanbhokai T: Lactose intolerance in Thailand. Nature 221:758-759, 1969 9. Elliott RB, Maxwell GM, Vawser N: Lactose maldigestion in Australian aboriginal children. Med J Aust 1:46-49, 1967 10. Rab SM, Baseer A: High intestinal lactase concentration in adult Pakistanis. Br Med J 1:436, 1976 11. McMichael HB, Webb J, Dawson AM: Jejunal disaccharidases and some observations on the cause oflactase deficiency. Br Med J 2:1037-1041, 1966 12. Huang SS, Bayless TM: Milk and lactose intolerance in healthy orientals. Science 160:83-84, 1968 13. Bolin TD, Crane CG, Davis AE: Lactose intolerance in various ethnic groups in South-east Asia. Australas Ann Med 17:300306, 1968 14. Alzate H, Gonzalez H, Guzman J: Lactose intolerance in South American Indians. Am J Clin Pathol 22:122-123, 1969

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15. Newcomer AD, McGill DB: Disaccharidase activity in the small intestine: prevalence of lactase deficiency in 100 healthy subjects. Gastroenterology 53:881-889, 1967 16. Bolin TD, Morrison RM, Steel JE, et al: Lactose intolerance in Australia. Med J Aust 1:1289-1291, 1970b 17. Gudmand-Hoyer E, Dahlqvist A, Jarnum S: Specific smallintestinal lactase deficiency in adults. Scand J Gastroenterol 4:377-386, 1969 18. Jussila J, Isokoski M, Launiala K: Prevalence 9flactose malabsorption in a Finnish rural population. Scand J Gastroenterol 5:49-56, 1970 19. Neale G: The diagnosis, incidence and significance of disaccharidase deficiency in adults. Proc R Soc Med 61:1099-1102, 1968 20. Simoons FJ: The traditional limits of milking and milk use in southern Asia. Anthropos 65:547-593, 1970 21. Varley H: In Practical Clinical Biochemistry. Third edition. London, William Heineman Ltd, 1963, P 35 22. Jussila J: Diagnosis of lactose malabsorption by the lactose tolerance test with peroral ethanol administration. Scand J GastroenteroI4:361-364, 1969 23. Roe JH, Rice EW: A photometric method for the determination of free pentoses in animal tissues. J BioI Chern 173:507-512, 1948 24. Dahlqvist A: Method for assay of intestinal disaccharidases. Anal Biochem 7:18-25, 1964 25. Haemmerli VP, Kistler H, Ammann R, et al: Acquired milk intolerance in the adult caused by lactose malabsorption due to a selective deficiency of intestinal lactase activity. Am J Med 38:730, 1965 26. Huang SS, Bayless TM: Lactose intolerance in healthy children. N Engl J Med 276:1283-1287, 1967 27. Jeejeebhoy KN, Desai HG, Verghese RV: Milk intolerance in tropical malabsorption syndrome. Role oflactose malabsorption. Lancet 2:666-668, 1966 28. Jersky J, Kinsley RH: Lactase deficiency in the South African Bantu. S Afr Med J 41:1194-1196, 1967 29. London DR, Cuatrecasas P, Birge SJ, et al: Metabolism of lactose by intestinal mucosa from normal and lactase-deficient subjects. Br J Med 1:524-526, 1967 30. Stodola FH, Lockwood LB: The oxidation of lactose and maltose to bionic acids by Pseudomonas. J BioI Chern 171:213-221,1947 31. Nishizuka Y, Hayaishi 0: Enzymic formation oflactobionic acid from lactose. J BioI Chern 237:2721-2728, 1962 32. McMichael HB, Webb J, Dawson AM: Lactase deficiency in adults. A cause of functional diarrhea. Lancet 1:717-720,1965