LACTOSE IS DIGESTED BY LACTASE in the intestine, a single epithelial cell of which is enlarged 37,500 diameters in this scan·
ning electron micrograph made by Jeanne M. Riddle of the Wayne
State University School of Medicine. The cell, on the surface of
one of the linger.like villi that stud the lining of the intestine, is
in turn covered by innumerable line processes called microvilli.
© 1972 SCIENTIFIC AMERICAN, INC© 1972 SCIENTIFIC AMERICAN, INC
LACTOSE AND LACTASE
Lactose is milk sugar; the enzyme lactase breaks it down. For want
of lactase most adults cannot digest milk. In populations that drink
milk the adults have more lactase, perhaps through natural selection
M ilk is the universal food of newborn mammals, but some human infants cannot digest it be cause they lack sufficient quantities of lactase, the enzyme that breaks down lactose, or milk sugar. Adults of all ani mal species other than man also lack the enzyme-and so, it is now clear, do most human beings after between two and four years of age. That this general adult deficiency in lactase has come as a surprise to physiologists and nutrition ists can perhaps be attributed to a kind of ethnic chauvinism, since the few hu man populations in which tolerance of lactose has been found to exceed in tolerance include most northern Euro pean and white American ethnic groups.
Milk is a nearly complete human food, and in powdered form it can be con veniently stored and shipped long dis tances. Hence it is a popular source of protein and other nutrients in many programs of aid to nutritionally impov erished children, including American blacks. The discovery that many of these children are physiologically intolerant to lactose is therefore a matter of concern and its implications are currently being examined by such agencies as the U.S. Office of Child Development and the Protein Advisory Group of the United Nations System.
Lactose is one of the three major solid components of milk and its only carbo hydrate; the other components are fats and proteins. Lactose is a disaccharide composed of the monosaccharides glu cose and galactose. It is synthesized only by the cells of the lactating mammary gland, through the reaction of glucose with the compound uridine diphosphate galactose [see illustrations on next page]. One of the proteins found in milk, alpha-lactalbumin, is required for the synthesis of lactose. This protein appar ently does not actually enter into the
by Norman Kretchmer
reaction; what it does is “specify” the action of the enzyme galactosyl trans ferase, modifying the enzyme so that in the presence of alpha-lactalbumin and glucose it catalyzes the synthesis of lactose.
In the nonlactating mammary gland, where alpha-lactalbumin is not present, the enzyme synthesizes instead of lac tose a more complicated carbohydrate, N-acetyl lactosamine. Test-tube studies have shown that alpha-lactalbumin is manufactured only in the presence of certain hormones: insulin, cortisone, es trogen and prolactin; its synthesis is in hibited by the hormone progesterone. It is when progesterone levels decrease late in pregnancy that the manufacture of alpha-lactalbumin, and thus of lac tose, is initiated [see “Milk,” by Stuart Patton; SCIENTIFIC AMERICAN, July, 1969].
The concentration of lactose in milk from different sources varies consider ably. Human milk is the sweetest, with 7.5 grams of lactose per 100 milliliters of milk. Cow’s milk has 4.5 grams per 100 milliliters. The only mammals that do not have any lactose-or any other carbohydrate-in their milk are certain of the Pinnipedia: the seals, sea lions and walruses of the Pacific basin. If these animals are given lactose in any form, they become sick. (In 1933 there was a report of a baby walrus that was fed cow’s milk while being shipped from Alaska to California. The animal suffered from severe diarrhea through out the voyage and was very sick by the time it arrived in San Diego.) Of these pinnipeds the California sea lion has been the most intensively studied. No alpha-lactalbumin is synthesized by its mammary gland. When alpha-lactalbu min from either rat’s milk or cow’s milk is added to a preparation of sea lion mammary gland in a test tube, however,
the glandular tissue does manufacture lactose.
In general, low concentrations of lac tose are associated with high concentra tions of milk fat (which is particularly useful to marine mammals). The Pa cific pinnipeds have more than 35 grams of fat per 100 milliliters of milk, com pared with less than four grams in the cow. In the whale and the bear (an an cient ancestor of which may also be an ancestor of the Pacific pinnipeds) the lactose in milk is low and the fat content is high.
�ctase, the enzyme that breaks down lactose ingested in milk or a milk
product, is a specific intestinal beta galactosidase that acts only on lactose, primarily in the jejunum, the second of the small intestine’s three main seg ments. The functional units of the wall of the small intestine are the villus (composed of metabolically active, dif ferentiated, nondividing cells) and the crypt (a set of dividing cells from which those of the villus are derived). Lactase is not present in the dividing cells. It appears in the differentiated cells, spe cifically within the brush border of the cells at the surface of the villus [see il lustrations on page 74]. Lactase splits the disaccharide lactose into its two component monosaccharides, glucose and galactose. Some of the released glu cose can be utilized directly by the cells of the villus; the remainder, along with the galactose, enters the bloodstream, and both sugars are metabolized by the liver. Neither Gary Gray of the Stan ford University School of Medicine nor other investigators have been able to distinguish any qualitative biochemical or physical difference among the lac tases isolated from the intestine of in fants, tolerant adults and intolerant adults. The difference appears to be
© 1972 SCIENTIFIC AMERICAN, INC© 1972 SCIENTIFIC AMERICAN, INC
LACTOSE, a disaccharide composed of the monosaccharides glucose and galactose, is the
carbohydrate of milk, the other major components of which are fats, proteins and water.
merely quantitative; there is simply very little lactase in the intestine of a lactose intolerant person. In the intestine of Pa cific pinnipeds, Philip Sunshine of the Stanford School of Medicine found, there is no lactase at all, even in infancy.
Lactase is not present in the intestine of the embryo or the fetus until the mid dle of the last stage of gestation. Its
activity attains a maximum immediate ly after birth. Thereafter it decreases, reaching a low level, for example, im mediately after weaning in the rat and after one and a half to three years in most children. The exact mechanism in volved in the appearance and disappear ance of the lactase is not known, but such a pattern of waxing and waning
I UDP-GALACTOSEI + ell G�L;!;U[g C:gO§:S�EII—-��–=�[1 h!LA�C�T�O�S§EI + I UDP I
I UDP-GALACTOSEj + r—–“—� LA�t’8§r�fNE + IUDPI ===..!:.!!:�
1r DI LA�C�TO�S�E�I————��——�»�I�G�LU�C�O�s�E I + �ACTOSE I SYNTHESIS OF LACTOSE in the mammary gland begins late in pregnancy when specific hormones and the protein alpha.lactalbumin are present. The latter modifies the enzyme galactosyl transferase, “specifying” it so that it catalyzes the synthesis of lactose from glu· cose and galactose (top). In the nonlactating gland the glucose takes part in a different reo action (middle). In intestine lactase breaks down lactose to glucose and galactose (bottom).
activity is common in the course of de velopment; in general terms, one can say that it results from differential ac tion of the gene or genes concerned.
Soon after the turn of the century the distinguished American pediatrician Abraham Jacobi pointed out that diar rhea in babies could be associated with the ingestion of carbohydrates. In 1921 another pediatrician, John Howland, said that “there is with many patients an abnormal response on the part of the intestinal tract to carbohydrates, which expresses itself in the form of diarrhea and excessive fermentation.” He sug gested as the cause a defiCiency in the hydrolysis, or enzymatic breakdown, of lactose.
The physiology is now well estab lished. If the amount of lactose present ed to the intestinal cells exceeds the hy drolytic capacity of the available lactase (whether because the lactase level is low or because an unusually large amount of lactose is ingested), a portion of the lac tose remains undigested. Some of it passes into the blood and is eventually excreted in the urine. The remainder moves on into the large intestine, where two processes ensue. One is physical: the lactose molecules increase the particle content of the intestinal fluid compared with the fluid in cells outside the intes tine and therefore by osmotic action draw water out of the tissues into the in testine. The other is biochemical: the glucose is fermented by the bacteria in the colon. Organic acids and carbon di oxide are generated and the symptoms can be those of any fermentative diar rhea, including a bloated feeling, flatu lence, belching, cramps and a watery, explosive diarrhea.
At the end of the 1950’s Paolo Du rand of the University of Genoa and Aaron Holzel and his colleagues at the UniverSity of Manchester reported de tailed studies of infants who were un able to digest lactose and who reacted to milk sugar with severe diarrhea, mal nutrition and even death. This work stimulated a revival of interest in lac tose and lactase, and there followed a period of active investigation of lactose intolerance. Many cases were reported, including some in which lactase inac tivity could be demonstrated in tissue taken from the patient’s intestine by biopsy. It became clear that intolerance in infants could be a congenital condi tion (as in Holzel’s two patients, who were Siblings) or, more frequently, could be secondary to various diseases and other stresses: cystic fibrosis, celiac disease, malnutrition, the ingestion of certain drugs, surgery and even non-
© 1972 SCIENTIFIC AMERICAN, INC© 1972 SCIENTIFIC AMERICAN, INC
specific diarrhea. During this period of investigation, it should be noted, in tolerance to lactose was generally as sumed to be the unusual condition and the condition worthy of study.
In 1965 Pedro Cuatrecasas and his colleagues and Theodore M. Bayless and Norton S. Rosensweig, all of whom were then at the Johns Hopkins School of Medicine, administered lactose to Amer ican blacks and whites, none of whom had had gastrointestinal complaints, and reported some startling findings. Where as only from 6 to 15 percent of the whites showed clinical symptoms of in tolerance, about 70 percent of the blacks were intolerant. This immediately sug gested that many human adults might be unable to digest lactose and, more specifically, that there might be signifi cant differences among ethnic groups. The possibility was soon confirmed: C. C. Cook and S. Kajubi of Makerere University College examined two differ ent tribes in Uganda. They found that only 20 percent of the adults of the cat tle-herding Tussi tribe were intolerant to lactose but that 80 percent of the non pastoral Canda were intolerant. Soon one paper after another reported a gen eral intolerance to lactose among many ethnic groups, including Japanese, other Orientals, Jews in Israel, Eskimos and South American Indians.
In these studies various measures of intolerance were applied. One was the appearance of clinical symptoms-flatu lence and diarrhea-after the ingestion of a dose of lactose, which was generally standardized at two grams of lactose per kilogram (2.2 pounds) of body weight, up to a maximum of either 50 or 100 grams. Another measure was a finding of low lactase activity (less than two units per gram of wet weight of tissue) deter mined through an intestinal biopsy after ingestion of the same dose of lactose. A third was an elevation of blood glu cose of less than 20 milligrams per 100 milliliters of blood after ingestion of the lactose. Since clinical symptoms are variable and the biopsy method is in convenient for the subject being tested, the blood glucose method is preferable. It is a direct measure of lactose break down, and false-negative results are rare if the glucose is measured 15 minutes after lactose is administered.
By 1970 enough data had been ac cumulated to indicate that many more groups all over the world are intolerant to lactose than are tolerant. As a matter of fact, real adult tolerance to lactose has so far been observed only in north ern Europeans, approximately 90 per cent of whom tolerate lactose, and in the
.CAMEL . jOW
5 LACTOSE (PERCENT)
i I , I
CONCENTRATION OF LACTOSE varies with the source of the milk. In general the less
lactose, the more fat, which can also be utilized by the newborn animal as an energy source.
5 1(\ 4
� 3 :> i= o « w (f)
� o 2 :5
o 10 o
DAYS BEFORE BIRTH
� — _. 20 30 40