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Disaccharidase Deficiency
Vol. 5-1, 1\0. 4, Part 2 of 2 Part,
GA:";TROf<;NTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
Printed in U.S.A.
DISACCHARIDASE DEFICIENCY In December 1962, editorial comment was made in this journaF that the clinical syndrome of sugar intolerance due to a deficiency of a specific disaccharidase activity in the small intestine may be relatively common. Scarcely 5 months later, the journal received two manuscripts 2 , 3 reporting on the occurrence of a specific deficiency of intestinal lactase in the otherwise nor-
mal human adult. Since that time, it has turned out 4 - 6 that this particular lesion is, indeed, common. It is present in as many as 70% of the individuals in some racial groups. It is the most prevalent of the disaccharidase deficiencies and may be expected to be encountered daily in practice. Dahlqvist, Hammond, Crane, Dunphy, and Littman3 wrote as follows:
INTESTINAL LACTASE DEFICIENCY AND LACTOSE INTOLERANCE IN ADULTS Prelilllinary Report ARNE DAHLQVIST, M.D., JAMES JAMES
V.
B.
HAMMOND, M.D., ROBERT
K.
CRANE, PH.D.,
DUNPHY, M.D., AND ARMAND LITTMAN, M.D.
Department of Bl:ochemistry, the Chicago Medical School, Chicago, and the Medical Service, Veterans Administration Hospital, Hines, Illinois
"In recent years a syndrome of lactose intolerance has been reported in children. 1-9 This syndrome is manifested by severe diarrhea with frothy stools containing lactose and lactic acid. It is usually accompanied by severe malnutrition, especially in the s~lall infant. These symptoms respond dramatically to the exelusion of lactose from the diet. Because of the presence of a flat blood sugar curve after the ingestion of lactose and a normal blood sugar rise after the ingestion of monosaccharides or other disaccharides, it has usually been inferred that the syndrome results from the absence of effective lactase activity in the intestinal epithelium. However, in no reported case have mucosal biopsy specimens been analyzed to support this inference by direct demonstration of diminished lactase activity. In view of the frequency of intolerance for milk among adults, we wished to learn whether this adult syndrome might also be an intolerance to lactose and be due to
deficient intestinal lactase activity. No follow-up observations which might show whether the presumed lactase deficit in lactose intolerant children is permanent have been reported. In the similar syndrome of sucrose and isomaltose intolerance, the d efec t seems t 0 d'Isappear grad ua11y WI'th maturity.l0-12" The data that they presented on 7 patients, 4 intolerant to milk plus 3 controls, were contained in their figure 1 and table 1. It was clear from these data that "the 3 patients with lactose-induced diarrhea and abdominal distress had flat lactose tolerance curves, normal glucose-galactose tolerance, and a severe deficit of lactase in the mucosal homogenates." They concluded as follows: "1. Intolerance for lactose has been shown to exist as a cause for milk intolerance in 3 adults. 2. Impaired digestion and absorption of 807
808
Vol. 54, .Yo . 4, Part 2
DISACCHARIDASE DEFICIEN CY 160 150 140
LACTOSE TOLERANCE
~
.;.
"
....'...,<;)~" .... <:> c::.
<;) <;)
....
~
130 120 110 100 90 80
o
30
90
60
o
120
30
60
90
120
MINUTeS
FIG. 1. Blood glucose curves after oral tolerance tests with lactose and a glucose-galactose mixture in the milk intolerant patients studied. Patients I, II, and III had a flat curve after lactose, but a normal rise after the glucose-galactose mixture. We interpret the slow rise in blood sugar level in patient I after the monosaccharides as possibly due to delayed gastric emptying. Patient IV had a normal blood glucose rise after lactose. TABLE 1 Disaccharidase activities of biopsy specimens of the small intestinal mucosa (obtained at the ligament of Treitz) Patients with milk intolerance
Case no. ....... . . .
Normal lactose
Abnormal lactose tolerance
..... I
I
II
I
Control cases
tolerance
III
A
B
C
6.6 5.6 6.6 20 .7
5.7 ll.6 13 .6 42.4
IV
Units of disaccharidase activity per gm. mucosa (wet wt.)G
Lactose .. . ... . . . . . Sucrase . ..... . . . . . . Isomal tase ... ... .. Maltase . .....
0.20 4.4 5 .1 19.5
0.36 8.5 8.4 31.8
<0.3 4 .9 4.7 28.3
6.9 ll.8 14.2 39.3
5.5 6.4 7.5 20.6
G Each figure is the mean of the results of t he assay of 2 or 3 separate biopsy specimens obtained on the same occasion.
lactose was caused by greatly reduced lactase activity in the intestinal mucosa of these patients. 3. Intestinal mucosal biopsy material is suitable for quantitative assay of disaccharidase activity."
The circumstances contributing to this description of adult lactase deficiency are interesting. " Fermentative diarrhea" was a concept known to certain perceptive physicians over 50 years ago. 6 However, not until 1958 and later was the etiology of
IlpI'ii196S
DI SA CCHA HI D.I SE DEFICIEX C Y
gastrointeE'tillal Hymptoms following the ingestion of sJlecific carbohydrates to become firmly haE'ed in a concept of the absence of a specific ellzyme from the mucosa of the small intestine. In the first place, methods for sampling of the intestinal mucosa by peroral biopsy 7 have only recently been developed and were not in widespread use until at least 1962. In the second place, it was not until 1961 that it was convincingly proved that the disaccharidases of the small intestine are not secreted into the lumen as part of a "succus entericus" but are actually present in the epithelial cell as firmly attached components of its brush border pole. With continued study of this organelle the membrane covering its projecting microvilli 8 has come to be understood as forming a digestive-absorptive surface. 9 Until this modern concept of location and function was established it was not obvious that assay of peroral biopsy samples would be a reliable index to intestinal disaccharide-splitting capacity. The occurrence of disaccharidase deficiencies in children had been adequately and widely described prior to 1963. Both lactase deficiency and a combined sucraseisomaltase deficiency had been documented by various groups, particularly in Holland, Switzerland, England, Italy, and Australia. Although the studies were inferential-that is, they were based on the response of the patient to dietary loads of individual disaccharides and the recovery of the un split offending disaccharide in the stool-there could be little doubt of their meaning. Confirmation by assay of biopsies was reported in 1963. The first documented cases of isolated lactase deficit in adults were also reported in 1963; the first documented case of sucrase-isomaltase deficit in an adult was reported in this journal somewhat later.Io In January 1963, there came together in Chicago several men whose combined knowledge made a collaborative effort in deliberate search for adult lactase deficit inevitable. Littman, Chief of the Medical Service at Hines Veterans Administration Hospital, and his young colleague, Dunphy, were concerned to know why many patients did not tolerate the milk so frequently pre-
80!)
scribed. Crane, in whose laboratories in St. Louis the brush border localization of disaccharidases had been discovered, held the Chair in Biochemistry at the Chicago Medical School and chose as his first Visiting Professor Arne Dahlqvist. Dahlqvist had not only made the special contributions of working out the specificity of the intestinal disaccharidases and developing convenient assays for each but had also worked with the group in Zurich on disaccharidase deficiency in children. Hammond, a gastroenterologist spending a postdoctorate year with Crane, made the contact between the two groups. The result of this contact has been described. Some months prior to the event in Chicago, a young woman giving a long history of milk intolerance with symptoms which became more severe following surgical removal of the entirety of her ileum came into the capable hands of Fred Kern and his colleagues in Denver. There followed an exceptionally detailed and well thought out study. Sugar tolerance was studied by duodenal instillation as well as by oral administration to obviate the possibility that the fiat curves obtained in response to lactose were due to delay in gastric emptying. The effect of individual milk components in the diet was studied and lactose was found to be the offender. Also, like the Chicago group, Kern and his colleagues performed jejunal biopsy to confirm the diagnosis. A portion of the biopsy was sent to Crane in Chicago for disaccharidase assay. Mischance intervened. The jejunum had, unfortunately, been perforated. 2 Further biopsies could not be taken. There was one specimen available and its large proportion of muscle tissue prevented the appropriate calculations to know for certain whether lactase activity which was low relative to the normal levels of sucrase and maltase was, in fact, lower than the level in some individuals who do not exhibit symptoms after lactose ingestion. 4 This rare accident prevented the positive documentation of lactase deficit in this otherwise thoroughly studied patient. 2 Isolated lactase deficiency in the adult may be considered to be a well documented
810
DISACCHARIDASE DEFICIESCY
entity4-6 in which the loss of lactase activity is not restricted to any particular portion of the small intestine. l l Some apparent lactase activity remains in mucosal biopsies taken from even those individuals most severely responsive to lactose ingestion. This anomaly appears to be explained, at least in part, by the presence of an additional ,B-galactosidase of presumed lysosomal origin. This ,B-galactosidase is not reduced in lactase deficiency 12 and probably does not function in lactose digestion. 12 , 13 The value of the lactose tolerance test for diagnosis of isolated lactase deficiency has been discussed at length in this journal. H , 15 Lactose intolerance also occurs in adult celiac disease. 16 However, this is not an isolated deficit; the other enzymes of the brush border are also reduced. Symptoms of sugar intolerance may, however, be relatively more easily induced by lactose in diseases causing mucosal damage owing to the limiting rate of lactose hydrolysis in the digestion and absorption of this sugarP R.EFER.ENCES 1. Dahlqvist, A. 1962. The intestinal disaccharidases and disaccharide intolerance. Gastroenterology 43: 694-696. 2. Kern, F., Jr., J. E. Struthers, Jr., and W. L. Atwood. 1963. Lactose intolerance as a cause of steatorrhea in an adult. Gastroenterology 45: 477-487. 3. Dahlqvist, A., J. B. Hammond, R.. K. Crane, J. V. Dunphy, and A. Littman. 1963. Intestinal lactase deficiency and lactose intolerance in adults. Gastroenterology 45: 488-491. 4. Dunphy, J. V., A. Littman, J. B. Hammond, G. Forstner, A. Dahlqvist, and R.. K. Crane. 1965. Intestinal lactase deficit in adults. Gastroenterology 49: 12-21. 5. Peternel, W. W. 1965. Lactose intolerance in
Yol. 54, No.4, Part;]
relation to intestinal lactase activity. Gastroenterology 48: 299-306. 6. Littman, A., and J. B. Hammond. 1965. Diarrhea in adults caused by deficiency in intestinal disaccharidases. Gastroenterology 48: 237-249. 7. R.ubin, C. E., and W. O. Dobbins, III. 1965. Peroral biopsy of the small intestine. Gastroenterology 49: 676-697. 8. Trier, J. S., and C. E. R.ubin. 1965. Electron microscopy of the small intestine: a review. Gastroenterology 49: 574-603. 9. Crane, R.. K. 1966. Enzymes and malabsorption: a concept of brush border membrane disease. Gastroenterology 50: 254-262. 10. Sonntag, W. M., M. L. Brill, W. G. Troyer, J. D. Welsh, G. Semenza, and A. Prader. 1964. Sucrose-isomaltose malabsorption in an adult woman. Gastroenterology 47: 18-25. 11. Newcomer, A. D., and D. B. McGrill. 1966. Distribution of disaccharidase activity in the small bowel of normal and lactase-deficient subjects. Gastroenterology 51: 481-488. 12. Zoppi, G., B. Hadorn, R.. Gitzelmann, H. Kistler, and A. Prader. 1966. Intestinal iJ-galactosidase activities in malabsorption syndromes. Gastroenterology 50: 557-561. 13. Koldovsky, 0., P. Sunshine, and N. Kretchmer. 1966. The digestion of carbohydrates during postnatal development. Gastroenterology 50: 595-599. 14. Newcomer, A. D., and D. B. McGill. 1966. Lactose tolerance tests in adults with normal lactase activity. Gastroenterology 50: 340-346. 15. Welsh, J. D. 1966. On the lactose tolerance test. Gastroenterology 51: 445-446. 16. Weser, E., and M. H. Sleisenger. 1965. Lactosuria and lactase deficiency in adult celiac disease. Gastroenterology 48: 571-578. 17. Gray, G. M., and N. A. Santiago. 1966. Disaccharide absorption in normal and diseased human intestine. Gastroenterology 51: 489498.
GA:";TROf<;NTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
Printed in U.S.A.
DISACCHARIDASE DEFICIENCY In December 1962, editorial comment was made in this journaF that the clinical syndrome of sugar intolerance due to a deficiency of a specific disaccharidase activity in the small intestine may be relatively common. Scarcely 5 months later, the journal received two manuscripts 2 , 3 reporting on the occurrence of a specific deficiency of intestinal lactase in the otherwise nor-
mal human adult. Since that time, it has turned out 4 - 6 that this particular lesion is, indeed, common. It is present in as many as 70% of the individuals in some racial groups. It is the most prevalent of the disaccharidase deficiencies and may be expected to be encountered daily in practice. Dahlqvist, Hammond, Crane, Dunphy, and Littman3 wrote as follows:
INTESTINAL LACTASE DEFICIENCY AND LACTOSE INTOLERANCE IN ADULTS Prelilllinary Report ARNE DAHLQVIST, M.D., JAMES JAMES
V.
B.
HAMMOND, M.D., ROBERT
K.
CRANE, PH.D.,
DUNPHY, M.D., AND ARMAND LITTMAN, M.D.
Department of Bl:ochemistry, the Chicago Medical School, Chicago, and the Medical Service, Veterans Administration Hospital, Hines, Illinois
"In recent years a syndrome of lactose intolerance has been reported in children. 1-9 This syndrome is manifested by severe diarrhea with frothy stools containing lactose and lactic acid. It is usually accompanied by severe malnutrition, especially in the s~lall infant. These symptoms respond dramatically to the exelusion of lactose from the diet. Because of the presence of a flat blood sugar curve after the ingestion of lactose and a normal blood sugar rise after the ingestion of monosaccharides or other disaccharides, it has usually been inferred that the syndrome results from the absence of effective lactase activity in the intestinal epithelium. However, in no reported case have mucosal biopsy specimens been analyzed to support this inference by direct demonstration of diminished lactase activity. In view of the frequency of intolerance for milk among adults, we wished to learn whether this adult syndrome might also be an intolerance to lactose and be due to
deficient intestinal lactase activity. No follow-up observations which might show whether the presumed lactase deficit in lactose intolerant children is permanent have been reported. In the similar syndrome of sucrose and isomaltose intolerance, the d efec t seems t 0 d'Isappear grad ua11y WI'th maturity.l0-12" The data that they presented on 7 patients, 4 intolerant to milk plus 3 controls, were contained in their figure 1 and table 1. It was clear from these data that "the 3 patients with lactose-induced diarrhea and abdominal distress had flat lactose tolerance curves, normal glucose-galactose tolerance, and a severe deficit of lactase in the mucosal homogenates." They concluded as follows: "1. Intolerance for lactose has been shown to exist as a cause for milk intolerance in 3 adults. 2. Impaired digestion and absorption of 807
808
Vol. 54, .Yo . 4, Part 2
DISACCHARIDASE DEFICIEN CY 160 150 140
LACTOSE TOLERANCE
~
.;.
"
....'...,<;)~" .... <:> c::.
<;) <;)
....
~
130 120 110 100 90 80
o
30
90
60
o
120
30
60
90
120
MINUTeS
FIG. 1. Blood glucose curves after oral tolerance tests with lactose and a glucose-galactose mixture in the milk intolerant patients studied. Patients I, II, and III had a flat curve after lactose, but a normal rise after the glucose-galactose mixture. We interpret the slow rise in blood sugar level in patient I after the monosaccharides as possibly due to delayed gastric emptying. Patient IV had a normal blood glucose rise after lactose. TABLE 1 Disaccharidase activities of biopsy specimens of the small intestinal mucosa (obtained at the ligament of Treitz) Patients with milk intolerance
Case no. ....... . . .
Normal lactose
Abnormal lactose tolerance
..... I
I
II
I
Control cases
tolerance
III
A
B
C
6.6 5.6 6.6 20 .7
5.7 ll.6 13 .6 42.4
IV
Units of disaccharidase activity per gm. mucosa (wet wt.)G
Lactose .. . ... . . . . . Sucrase . ..... . . . . . . Isomal tase ... ... .. Maltase . .....
0.20 4.4 5 .1 19.5
0.36 8.5 8.4 31.8
<0.3 4 .9 4.7 28.3
6.9 ll.8 14.2 39.3
5.5 6.4 7.5 20.6
G Each figure is the mean of the results of t he assay of 2 or 3 separate biopsy specimens obtained on the same occasion.
lactose was caused by greatly reduced lactase activity in the intestinal mucosa of these patients. 3. Intestinal mucosal biopsy material is suitable for quantitative assay of disaccharidase activity."
The circumstances contributing to this description of adult lactase deficiency are interesting. " Fermentative diarrhea" was a concept known to certain perceptive physicians over 50 years ago. 6 However, not until 1958 and later was the etiology of
IlpI'ii196S
DI SA CCHA HI D.I SE DEFICIEX C Y
gastrointeE'tillal Hymptoms following the ingestion of sJlecific carbohydrates to become firmly haE'ed in a concept of the absence of a specific ellzyme from the mucosa of the small intestine. In the first place, methods for sampling of the intestinal mucosa by peroral biopsy 7 have only recently been developed and were not in widespread use until at least 1962. In the second place, it was not until 1961 that it was convincingly proved that the disaccharidases of the small intestine are not secreted into the lumen as part of a "succus entericus" but are actually present in the epithelial cell as firmly attached components of its brush border pole. With continued study of this organelle the membrane covering its projecting microvilli 8 has come to be understood as forming a digestive-absorptive surface. 9 Until this modern concept of location and function was established it was not obvious that assay of peroral biopsy samples would be a reliable index to intestinal disaccharide-splitting capacity. The occurrence of disaccharidase deficiencies in children had been adequately and widely described prior to 1963. Both lactase deficiency and a combined sucraseisomaltase deficiency had been documented by various groups, particularly in Holland, Switzerland, England, Italy, and Australia. Although the studies were inferential-that is, they were based on the response of the patient to dietary loads of individual disaccharides and the recovery of the un split offending disaccharide in the stool-there could be little doubt of their meaning. Confirmation by assay of biopsies was reported in 1963. The first documented cases of isolated lactase deficit in adults were also reported in 1963; the first documented case of sucrase-isomaltase deficit in an adult was reported in this journal somewhat later.Io In January 1963, there came together in Chicago several men whose combined knowledge made a collaborative effort in deliberate search for adult lactase deficit inevitable. Littman, Chief of the Medical Service at Hines Veterans Administration Hospital, and his young colleague, Dunphy, were concerned to know why many patients did not tolerate the milk so frequently pre-
80!)
scribed. Crane, in whose laboratories in St. Louis the brush border localization of disaccharidases had been discovered, held the Chair in Biochemistry at the Chicago Medical School and chose as his first Visiting Professor Arne Dahlqvist. Dahlqvist had not only made the special contributions of working out the specificity of the intestinal disaccharidases and developing convenient assays for each but had also worked with the group in Zurich on disaccharidase deficiency in children. Hammond, a gastroenterologist spending a postdoctorate year with Crane, made the contact between the two groups. The result of this contact has been described. Some months prior to the event in Chicago, a young woman giving a long history of milk intolerance with symptoms which became more severe following surgical removal of the entirety of her ileum came into the capable hands of Fred Kern and his colleagues in Denver. There followed an exceptionally detailed and well thought out study. Sugar tolerance was studied by duodenal instillation as well as by oral administration to obviate the possibility that the fiat curves obtained in response to lactose were due to delay in gastric emptying. The effect of individual milk components in the diet was studied and lactose was found to be the offender. Also, like the Chicago group, Kern and his colleagues performed jejunal biopsy to confirm the diagnosis. A portion of the biopsy was sent to Crane in Chicago for disaccharidase assay. Mischance intervened. The jejunum had, unfortunately, been perforated. 2 Further biopsies could not be taken. There was one specimen available and its large proportion of muscle tissue prevented the appropriate calculations to know for certain whether lactase activity which was low relative to the normal levels of sucrase and maltase was, in fact, lower than the level in some individuals who do not exhibit symptoms after lactose ingestion. 4 This rare accident prevented the positive documentation of lactase deficit in this otherwise thoroughly studied patient. 2 Isolated lactase deficiency in the adult may be considered to be a well documented
810
DISACCHARIDASE DEFICIESCY
entity4-6 in which the loss of lactase activity is not restricted to any particular portion of the small intestine. l l Some apparent lactase activity remains in mucosal biopsies taken from even those individuals most severely responsive to lactose ingestion. This anomaly appears to be explained, at least in part, by the presence of an additional ,B-galactosidase of presumed lysosomal origin. This ,B-galactosidase is not reduced in lactase deficiency 12 and probably does not function in lactose digestion. 12 , 13 The value of the lactose tolerance test for diagnosis of isolated lactase deficiency has been discussed at length in this journal. H , 15 Lactose intolerance also occurs in adult celiac disease. 16 However, this is not an isolated deficit; the other enzymes of the brush border are also reduced. Symptoms of sugar intolerance may, however, be relatively more easily induced by lactose in diseases causing mucosal damage owing to the limiting rate of lactose hydrolysis in the digestion and absorption of this sugarP R.EFER.ENCES 1. Dahlqvist, A. 1962. The intestinal disaccharidases and disaccharide intolerance. Gastroenterology 43: 694-696. 2. Kern, F., Jr., J. E. Struthers, Jr., and W. L. Atwood. 1963. Lactose intolerance as a cause of steatorrhea in an adult. Gastroenterology 45: 477-487. 3. Dahlqvist, A., J. B. Hammond, R.. K. Crane, J. V. Dunphy, and A. Littman. 1963. Intestinal lactase deficiency and lactose intolerance in adults. Gastroenterology 45: 488-491. 4. Dunphy, J. V., A. Littman, J. B. Hammond, G. Forstner, A. Dahlqvist, and R.. K. Crane. 1965. Intestinal lactase deficit in adults. Gastroenterology 49: 12-21. 5. Peternel, W. W. 1965. Lactose intolerance in
Yol. 54, No.4, Part;]
relation to intestinal lactase activity. Gastroenterology 48: 299-306. 6. Littman, A., and J. B. Hammond. 1965. Diarrhea in adults caused by deficiency in intestinal disaccharidases. Gastroenterology 48: 237-249. 7. R.ubin, C. E., and W. O. Dobbins, III. 1965. Peroral biopsy of the small intestine. Gastroenterology 49: 676-697. 8. Trier, J. S., and C. E. R.ubin. 1965. Electron microscopy of the small intestine: a review. Gastroenterology 49: 574-603. 9. Crane, R.. K. 1966. Enzymes and malabsorption: a concept of brush border membrane disease. Gastroenterology 50: 254-262. 10. Sonntag, W. M., M. L. Brill, W. G. Troyer, J. D. Welsh, G. Semenza, and A. Prader. 1964. Sucrose-isomaltose malabsorption in an adult woman. Gastroenterology 47: 18-25. 11. Newcomer, A. D., and D. B. McGrill. 1966. Distribution of disaccharidase activity in the small bowel of normal and lactase-deficient subjects. Gastroenterology 51: 481-488. 12. Zoppi, G., B. Hadorn, R.. Gitzelmann, H. Kistler, and A. Prader. 1966. Intestinal iJ-galactosidase activities in malabsorption syndromes. Gastroenterology 50: 557-561. 13. Koldovsky, 0., P. Sunshine, and N. Kretchmer. 1966. The digestion of carbohydrates during postnatal development. Gastroenterology 50: 595-599. 14. Newcomer, A. D., and D. B. McGill. 1966. Lactose tolerance tests in adults with normal lactase activity. Gastroenterology 50: 340-346. 15. Welsh, J. D. 1966. On the lactose tolerance test. Gastroenterology 51: 445-446. 16. Weser, E., and M. H. Sleisenger. 1965. Lactosuria and lactase deficiency in adult celiac disease. Gastroenterology 48: 571-578. 17. Gray, G. M., and N. A. Santiago. 1966. Disaccharide absorption in normal and diseased human intestine. Gastroenterology 51: 489498.