Hypolactasia and Lactase Persistence

Historical Review and the Terminology

T. SAHI
Dept. of Public Health, University of Helsinki, and Headquarters of the Frontier Guard, Helsinki,
Finland

Sahi T. Hypolactasia and lactase persistence. Historical review and the terminology. %and J Gastro-
enterol 19!44;29 Suppl202:1-6.
Lactase (more precisely lactase-phlorizinhydrolase) is located in the brush border of the small intestinal
enterocytesand is responsible for the hydrolysis of dietary lactose. The earliest studieson lactase activity
in mammals were published around the turn of the century. In 1903, it was found that the dog had a
very low lactase activity and therefore lactose remained unhydrolysed, causing diarrhoea. Human
hypolactasia was demonstrated in 1%3, and it was soon found that it is very common, commoner than
lactase persistence in most parts of the world. In 1973, adult-type hypolactasia was shown to be inherited
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by an autosomal recessive single gene. This article reviews the early expansion of the knowledge on
lactase and hypolactasia as well as the correct terminology.
Key words: Beta-galactosidase; hypolactasia; lactose; lactose intolerance
Tim0 Sahi, M.D.,S.M.,Headquarters of the Frontier Guard, P. 0. Box 3, SF-00131 Helsinki, Finland

Several enzymes or enzyme complexes are located in the This article reviews the early expansion of the knowledge
brush border (microvilli) of the mammalian small intestinal on intestinal lactase and the stability of its activity (lactase
enterocytes. One of them is lactase, which is PD-galac- persistence/hypolactasia) as well as the correct terminology
For personal use only.

tosidase. More precisely, it is now called lactase-phlorizin related to hypolactasia.

hydrolase (LPH) because it has two catalytic sites. One site,
the lactase proper (EC 3.2.1.23), splits lactose. The other
EARLY OBSERVATIONS ON INTESTINAL
site, phlorizin hydrolase, splits aryl- and alkyl-/%glycosides
LACTASE ACTIVITY
such as phlorizin and Fglycosylceramides. It has in fact two
enzyme activities, phlorizin hydrolase (EC 3.2.1.62) and It has long been known that milk may produce loose stools
glycosylceramidase (EC 3.2.1.45-46). The molecular weight or diarrhoea. Therefore many populations have considered
of the enzyme is 160,000kDa (see e.g. 42, 75, 100). milk unsuitable for consumption after weaning (49). Almost
Lactase is responsible for the hydrolysisof dietary lactose. 2000 years ago, Galen knew that milk was laxative and could
It has a typical activity pattern during animal life. This also cause other gastrointestinalsymptoms for some people
activity increases in late gestation and remains at a high level (47)*
until weaning, when it declines and is very low in adult In the 1860s it was discovered that it was milk sugar
mammals. In a great number of humans, the activity persists (lactose) which produced diarrhoea in dogs (9). The patho-
to adulthood and to the end of life (lactase persistence). In physiologic mechanism of this condition was only demon-
the majority of humans, however, the activity declines in strated in 1903 by Rohmann & Nagano (92), who found
the same way as in mammals to one-tenth of previous activity that, in the dog, unhydrolysed lactose molecules remained in
(hypolactasia). The decline takes place at between 2 and 20 the lumen of the small intestine for some time and produced
years of age (42, 94). a strong osmotic effect and diarrhoea. Lactose remained
There are also two other enzymes with Pgalactosidase unhydrolysed because the small intestine had a very low
activity: lysosomal acid-Fgalactosidase and cytoplasmic lactase activity. This observation was confirmed in humans
hetero-Fgalactosidase. These are found in other organs, by more sophisticated methods in the 1950s and 1960s (38,
too, and they play a very minor role in the hydrolysis of 61, 71).
ingested lactose. The latter has only in vitro activity (4). The Soon after the first observations of lactase activity (or in
deficiency of acid-/%galactosidaseis a rare inborn error of fact lactose hydrolysing capacity) in the small intestine in
metabolism. Its manifestations vary from severe mental the 1890s (28,36), it was found that activity could in general
retardation and death in infancy to a more benign adult be demonstrated only in young animals, not in old animals
type. In patients there is no ability to split galactose from (76, 81, 91). In one study, however, lactase activity was
proteoglycans, glycosaminoglycans and GM1 ganglioside found in old animals, too (109). Around the turn of the
(107). century there were only very few direct observations of
 2 T. Sahi

human small-intestinal lactase activity (70,82). Activity was the change in lactase activity did not satisfy the criteria of
found during infancy, but it was sharply reduced by severe substrate-inducedenzymatic adaptation, and considered her
diseases (82). findingsan example of metabolic adaptation. Further experi-
The principal site of activity seemed to be the small- ments prior to 1964 reported no adaptation (1, 29, 30).
intestinal mucosa (37, 81, 82, 86, 87). Activity was highest
in the jejunum and decreased towards the ileum. There Later animal feeding experiments
remained some controversy over lactase activity in the small- In the 1960s Dahlqvist developed an enzymatic method
intestinal juice, succus entericus: while some authors found for determining intestinal disaccharidase levels. This was
activity (a), others did not (50,92).Although some studies more accurate than the former reduction method (23, 24),
(M),particularly those by Cajori in the 1930s (16, 17), allowing smaller amounts and changes of lactase activity to
showed unequivocally that lactose was hydrolysed in the be identified.
small-intestinal epithelium and that there was only insig- After this method was introduced, several studiesreported
nificant activity in the succus entericus, many later textbooks an adaptive change in jejunal lactase activity. In 1964, Gir-
stated that the only site of lactase enzyme was the intestinal ardet et al. (46)found an increase in the lactase activity of
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juice (52, 80,108, 113). It was not until the late 1950s and rats after 6-9 weeks of 25% lactose in the diet, and Huber
early 196Os, with the publications of Borgstriim et al. (14) et al. (57) found similar results in 24 calves fed on increasing
and Dahlqvist et al. (26), that it became generally accepted amounts of lactose for 11 weeks. Cain et al. (16) fed rats on
that the hydrolysis of lactose takes place in the outer mem- a diet containing 60% lactose, and after 5 to 7 weeks
brane (brush border) of the mucosal epithelial cells and not observed an adaptation. Bolin et al. (11, 12) made the same
in the small intestinal juice, where lactase activity is very finding using 30% lactose in the diet. Other authors reported
low and of no practical importance. At least in children, similar findings (15, 86). However, these changes in lactase
however, it may reflect also the activity of brush border activity-an increase of about 50% and a decrease of less
lactase (2). than 40%-were small in comparison with the postweaning
decline in lactase activity (1, 12, 30). Since the differences
For personal use only.

in the lactase activity of old and infant animals were about

ADAPTNE CHANGES IN ANIMAL LACTASE
10-fold (15), one would also expect to see major differences
ACTIVITY
in feeding experiments if lactase were adaptive.
Early experiments to affect lactare activity Many other studies were unable to demonstrate any a d a p
The first experiments attempting to affect the intestinal tation of lactase, although they used rats (8, 65,66,73, 74,
activity of lactase were performed soon after the discovery 105), calves (101) and pigs (32,33) as experimental animals.
of this enzyme. Lactose was fed to animals for time periods Wen et al. (112) reported an adaptation of lactase after four
ranging from a few days to a few months. Generally, no months of lactose diet in certain monkey species, while in
change was found in lactase activity (81,85), although there others no adaptation could be demonstrated. Ferguson et
were also authors who reported opposite results (109). al. (35) implanted isograftsof fetal mouse intestine into adult
In 1896, Fischer & Niebel(37) suggested that there might mice and demonstrated that the implanted mouse intestine
occuf a process of lactase adaptation in old animals after developed the same kind of lactase pattern as the normal
prolonged periods of feeding on milk. Weinland demon- mouse intestine does after birth, even though it was never
strated in 1899 (109) that milk consumption continuing for exposed to food.
several months after the suckling period produced lactase There was no evidence that lactose feeding prevents the
activity in rabbits. However, most authors found that lactose normal postweaning decline of lactase activity (1, 12, 73).
feeding did not provoke lactase activity in the animal small However, some results suggested that the decline might start
intestine. Orban fed rabbits for 4 days (81), Bainbridge fed later in animals that are given lactose continuously after
dogs (7), and in 1906 Plimmer (85) reported the results of weaning than in those deprived of lactose (11, 73).
long-lasting experiments in rabbits, rats and other animals. In addition, it has been found that the effect of lactose is
All of them concluded that no adaptation occurs. non-specific in animals, because lactose-rich and lactose-
After these early experiments, no new work was reported deficient diets also affect sucrase and maltase levels, and
until Fischer et al. concluded in 1949 that no adaptive change glucose feeding increases lactase activity (12).
occurs in lactase activity (39, 40). In 1951, Heilskov (51)
showed that lactose feeding of rabbits did not prevent the
HUMAN LACTASE ACTIVITY
normd decline of lactase activity after weaning. In 1957,
F i s c h reported some interesting findings (38). She found Hypolactasia in man
a 50% mcrease in the lactase activity of rats that had been Reduced activity of lactase was not known to be of any
fed on lactose, but this increase was not significantly higher clinical importance in man, although early in this century it
than the change observed in the reference rats when cal- was found that lactose occasionally caused diarrhoea in
culating per unit of tissue nitrogen. Fischer concluded that infants (58,99). In the 1920s Howland stated that ‘there is
 Hypolactasia and Lactase Persktence 3

with many patients an abnormal response on the part of the reported similar results from Singapore (19), while other
intestine to carbohydrates, which expresses itself in the form studies supported these findings (88, 90).
of diarrhea and excessive fermentation. Such patients may
have some deficit in the ferments necessary for the hydrolysis Evidence for the non-adaptive nature of human lactase
of lactose’ (56). In addition to these feeding experiments, there was a
In 1959, Holzel et al. (55) described two siblings who had growing body of evidence that lactose in the human diet does
watery diarrhoea from birth and a very low lactase activity not prevent the manifestation of hypolactasia in childhood or
in the small intestine. Diarrhoea was induced by unabsorbed adolescence, and that lack of lactose does not cause lactase
lactose. Subsequently, other reports appeared of infants and activity to decline. There were observations that selective
children with congenitally low lactase activity (54, 72). hypolactasia had developed even during the suckling period
In 1963, Auricchio et al. (6) and Dahlqvist et al. (27) (20, 64)and in children who had regularly consumed large
independently described adults who had low small-intestinal quantities of milk after weaning (62, 95). Sahi & Launiala
lactase activity which was not, on the basis of case histories, reported four Finnish teenagers (97,98) who had consumed
congenital but had decreased since birth, as in animals. considerable amounts of milk since weaning. At the ages of
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These and later observations disproved the previous view 7, 10,13 and 14 years, they were lactose absorbers, while 5
that intestinal lactase activity remains high throughout the years later they had developed selective hypolact&ia in spite
human life-span. On the contrary, it was discovered that low of regular milk consumption of 2-5 glasses/day. On the
lactase activity (hypolactasia) is prevalent in adulthood in contrary, subjectswho had stopped drinking milk at weaning
the greatest part of humankind (51, 59,77, 102-104). It was but who had not developed hypolactasia were described (43,
found that the prevalence of hypolactasia is high in the 93). Flatz et al. found a Thai family (43) in which none of
geographical areas where adults do not consume milk and the family members had ever drunk milk after weaning;
vice versa (51,59,77,103). The age when adult hypolactasia some of them had selective lactose malabsorption, while
appears was found to range from age 1-2 (20,62) to 20 years others did not.
(93-95, 98). The negative results of human feeding experiments and
For personal use only.

the few early family studies (34, 41,43, 78, 111) supported
Adaptive changes in human lactase the hypothesis that the decline in lactase activity from the
No reports were published on the effects of dietary lactose high level to the level of hypolactasia may be genetically
on lactase activity in man before the 1960s. The first reported determined at least in man. This hypothesis was verified in
experiment was by Cuatrecasas et al. in 1965 (22). Seven the 1970s by Sahi et al. (96) and by Sahi (93) in his major
people with hypolactasia were given 150 g of lactose every Finnish family study.
day for 45 days without any evidence of an increase in
lactase activity. Rather the contrary, the authors observed a
THE TERMINOLOGY
significant decline in lactose absorption capability in two
subjects who were deprived of milk for 5 months. Knudsen Reporting on lactose hydrolysis (digestion) and lactase
et al. (67) fed seven subjects with normal lactase activity for activity remains surrounded by terminological inaccuracy
the same period of time as Cuatrecasas. In two subjects an and ambiguity. The recommended correct terminology is as
increase of 2 5 4 % was found, in three the activity decreased follows (94).
by 50%, and in one subject the level remained unchanged. Hypolactasia means a very low activity of lactase in the
In one minor experiment comprising only two subjects (79) jejunal mucosa. The most accurate method for determining
and in another comprising only one subject (89), no change this activity is a direct assay of lactase, e.g. from a jejunal
was observed in jejunal lactase activity after a lactose feeding biopsy sample (72, 79). As it may be felt that the term
of 10 and 14 days, respectively. A similar result was reported hypolactasia calls for ‘hyperlactasia’as its counterpart, Flak
in a larger study in which 50 male Thais with hypolactasia (42) recommends the term lactare restriction rather than
were fed 50 g/day of lactose for 26 days (63). On the other hypolactasia. Both terms describe the enzyme activity in a
hand, fasting was found to produce a decline in lactase proper way and both can be used. Hypolactasia is more
activity (67), but this was unspecific because a decrease was common. The terms lactase deficiency and aiactasia imply a
also observed in the activities of other disaccharidases. total lack of lactase activity, which does not necessarily
Suspectingthat earlier feeding experiments in humans had happen even in the case of a congenital disorder when lactase
not been of sufficientlylong duration, Kretchmer (69), Gilat activity is generally much lower than in the adult type (5).
(44)and Gilat et al. (45) organized experiments which lasted The limit between low lactase activity in people with
for 6 months and from 6 to 14 months, respectively. Kretch- hypolactasia and moderate lactase activity in people with
mer was unable to increase the lactose absorption ability of lactase persistence is arbitrary and differs somewhat between
Nigerian medical students who had hypolactasia, and Gilat different laboratories. However, the distribution of lactase
et al. found no change in jejunal lactase activity in Jews activity values is bimodal, implying two categories, i.e. those
even after a 1-year period of lactose feeding. Chua & Seah with hypolactasia and those with moderate or high (‘normal’)
 activity. Although there is some overlap between these adults with and without lactase deficiency. Scand J Gastro-
enterol 1971;6:755-62.
categories, it is possible to identify subjects of hypolactasia 5. Asp N-G, Dahlqvist A, Kuitunen P, Launiala K, Visakorpi
quite reliably (3, 25, Kari Launiala, unpublished obser- JK. Complete deficiency of brush-border lactase in congenital
vations). lactose malabsorption. Lancet 1973;2:329-30.
6. Auricchio S , Rubino A, Landolt M, Semenza G, Prader A.
Because it is inconvenient to take small intestinal biopsies Isolated intestinal lactase deficiency in the adult. Lancet 1963;
for lactase activity determinations, a lactose tolerance (load- 2~324-6.
ing) test was developed to verify hypolactasia or, in fact, the 7. Bainbridge FA. On the adaptation of the pancreas, J Physiol
(Lond) 1904;31:98-119.
ability of the small intestinal mucosa to hydrolyse and absorb 8. Becker A, Cerda R, Delgado P, Orrego-Matte H , Navia E.
lactose (13, 31, 41, 48, 60, 79, 110). The terms lactose Lack of effect of rat milk on intestinal lactase activity in the
malabsorption and lactose maldigestion describe a poor lac- postweaning rat. Acta Physiol Latinoam 1974;24:662-5.
9. Bischoff TLW, Voit C. Die Gesetze der Ernuhrung des Fleixh-
tose hydrolysing capacity which can be demonstrated, e.g. fressers durch neue Untersuchungen. Leipzig und Heidelberg:
as a small rise in blood glucose or in blood glucose and C.F. Winter'sche Verlagshandlung, 1860.
galactose concentration in the lactose tolerance test. It 10. Bolin TD, Davis AE. Primary lactase deficiency: genetic or
acquired? Am J Dig Dis 1970;15:679-92.
almost always implies hypolactasia, often making these terms
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11. Bolin TD, McKern A, Davis AE. The effect of diet on lactase
interchangeable (31, 60, 79). Flaw recommends the term activity in the rat. Gastroenterology 1971;60:432-7.
low lactose digestion capacity and as its counterpart high 12. Bolin TD, Puola RC, Davis AE. Adaptation of intestinal
lactase in the rat. Gastroenterology 1969;57:40&9.
lactose digestion capacity (42). Although these are proper 13. Borgstrom B, Dahlqvist A, Hambraeus L, editors. Intestinal
and accurate terms, they are somewhat cumbersome to use. enzyme deficiences and their nutritional implications. Sym-
In the literature the term lactose intolerance is often used posia of the Swedish Nutrition Foundation XI. Uppsala:
Almqvist & Wiksell, 1973.
to mean lactose malabsorption (or low lactose hydrolysing 14. Borgstrom BA, Dahlqvist A, Lundh G, Sjovall J. Studies of
capacity), because subjects with lactose malabsorption gen- digestion and absorption in the human. J Clin Invest 1957;
erally do not tolerate lactose, but have abdominal symptoms. 361521-36.
15. Broitman SA, Thalenfeld BE, Zamcheck N. Alterations in gut
However, some people with lactose malabsorption are very lactase activity in young and adult rats fed lactose (abstract).
asymptomatic and there are people who cannot tolerate Fed Proc 1968;27:573.
For personal use only.

lactose, although lactose is hydrolysed and absorbed (31, 16. Cain GD, Moore P, Patterson M, McElveen MA. The stimu-
lation of lactase by feeding lactose. Scand J Gastroenterol
93). Therefore the term lactose intolerance should be 1%9;4:54>50.
avoided when speaking about lactose malabsorption in gen- 17. Cajori FA. The enzyme activity of dogs intestinal juice and its
eral, but used about aclinical entity, i.e. symptomatic lactose relation to intestinal digestion. Am J Physiol 1933;104:659-68.
18. Cajori FA. The lactase activity of the intestinal mucosa of the
malabsorption. dog and some characteristics of intestinal lactase. J Biol Chem
The term milk intolerance means that a person suffers 1935;109:15943.
from abdominal symptoms after milk ingestion. However, 19. Chua KL, Seah CS. Lactose intolerance: hereditary or
acquired? Effect of prolonged milk feeding. Singapore Med J
one should remember that very often this does not mean 1973:14:2%33.
that the cause is lactose malabsorption. 20. Cook GC. Lactase activity in newborn and infant Baganda. Br
Hypolactasia and lactose malabsorption may appear sec- Med J 1%7;1:527-30.
21. Cook GC, Lee FD. The jejunum after kwashiorkor. Lancet
ondarily during infection or infestation of the small intestine, 1966;2:1263-7.
in coeliac disease (60, 93), protein joule malnutrition or 22. CuatrecasasP, Lockwood DH, Caldwell JR. Lactase deficiency
in the adult: a common occurrence. Lancet 1965;1:14-8.
kwashiorkor (10, 21, 106). In these cases the histological 23. Dahlqvist A. Determination of maltase and isomaltase activi-
structure of the intestine is often abnormal. Therefore a ties with a glucose-oxidase reagent. Biochem J 1%1;80:547-
secondary decrease in lactase activity (secondary hypo- 51.
24. Dahlqvist A. Method for assay of intestinal disaccharidases.
lactasia) and secondary lactose malabsorption should be Anal Biochem 1964;7:18-25.
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27. Dahlqvist A, Hammond JB, Crane RK, Dunphy JV, Littman
A. Intestinal lactase deficiency and lactose intolerance in
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