Lactose is a disaccharide composed of linked molecules of the simple sugars glucose and galactose. Dietary lactose is obtained almost exclusively from milk. Infants and young children digest lactose with an enzyme, lactase, which splits the molecule into the two readily absorbable simple sugars. The majority of adults, however, have lost this ability and are lactose malabsorbers. Those malabsorbers who display clinical symptoms after milk consumption are described as lactose intolerant.

Lactose is a major constituent of the milk of all mammals except sea lions (Kretchmer 1993). Human milk contains the highest lactose concentration, about 7 percent; lactose levels in commonly milked animals, such as camels, goats, sheep, and cows, run between 4 and 5 percent. Adult animals, like most humans, lose the ability to digest lactose. This suggests that adult loss of lactase is a normal mammalian trait and that adult ability to split lactose is an "abnormal" evolutionary innovation.

Definition and History

Lactose malabsorption and intolerance must be distinguished clinically from allergy to milk proteins, which is a rare but serious genetic problem in infants. This essay focuses on primary adult onset lactase deficiency, but two other forms of the syndrome must be noted. Lactase deficiency may be secondary due to damage to the small intestine from heavy parasitic infections (especially the protozoan Giardia lamblia); to other severe intestinal infections; to AIDS; and to ionizing radiation, some drugs, and gastric surgery (Castiglia 1994; Tamm 1994). Total inability to synthesize lactase is another rare genetic disorder that was obviously lethal until modern times. If diagnosed promptly, such cases can now be managed with soy-based infant formulas.

Gastrointestinal distress in adults after milk consumption was described in ancient Greek and Roman texts, and there were isolated clinical reports in the late nineteenth and early twentieth centuries, but the problem was not widely studied until the development (in the 1960s) of new techniques to study enzymatic action in the intestine. Consequently, the high prevalence of diminished lactase activity in healthy adults was described only in the early 1960s, with especially important work done by A. Dahlqvist and his associates (Dahlqvist 1977). Worldwide surveys in the 1960s and 1970s showed that loss of lactase activity in adulthood is the common condition in humans and that terms like "lactase deficient" incorrectly imply that this is somehow abnormal (Flatz 1987).

Biology and Clinical Manifestations

Lactase (technically lactase-phlorizin hydrolase), is a protein produced in the cells of the epithelium of the small intestine. It is most concentrated in the mucosal cells of the brush border of the jejunum (Buller and Grand 1990). Production of lactase begins to decline in most children between the ages of 2 to 5, around the time of weaning. Most adults retain only about 10 percent of infant-level lactase activity. But Finnish children who become lactase deficient often do so as teenagers; the reasons for this late onset are unknown (Arola and Tamm 1994).

If lactose-intolerant people consume significant quantities of milk or other dairy products, unmetabolized lactose passes through the small intestine to the large intestine, where it is acted upon by the resident facultative bacterial flora. These bacteria split lactose into acetic, butyric, propionic, and other short-chain fatty acids, which can be absorbed by intestinal cells and used as metabolites. Among the by-products are carbon dioxide, hydrogen, and methane, which can cause a gassy, bloated, and/or nauseous feeling.

It is generally thought that the abundance of short-chain molecules increases osmotic pressure within the intestinal lumen, causing water to pass into the lumen, sometimes in amounts that produce diarrhea (Castiglia 1994), but this has recently been questioned by H. Arola and A. Tamm (1994). They suggest that bacteria that produce larger amounts of iso-fatty acids — those with branched carbon chains in contrast to the normal straight chain forms — may provide protection against diarrhea. Although the intestinal flora of an individual tend to remain relatively stable over time, commensal bacterial populations vary considerably among people. Those persons with large colonies of the types of bacteria that efficiently metabolize lactose and produce significant quantities of iso-fatty acids (for example, members of the genus Bacteriodes) would be less likely to display symptoms (Arola and Tamm 1994). They would be lactose malabsorbers but not necessarily lactose intolerant.

Genetics

The mechanisms controlling lactase production were disputed for many years. Some researchers, drawing on studies of gene regulation in bacteria, argued in the 1960s that lactase was a substrate-inducible enzyme; that is, that lactase production was believed to be stimulated by the presence of its substrate, lactose. In this view, populations that did not use milk as adults lost the ability to produce lactase, whereas groups that did consume milk and milk products retained lactase capability.

Biochemical studies cast doubt on this theory, and family studies have demonstrated that lactase production is controlled by an autosomal gene, recently located on chromosome 2. Persistence of lactase production is a dominant trait (Buller and Grand 1990; Arola and Tamm 1994). Following the terminology suggested by Gebhard Flatz (1987), the two alleles are designated LAC*P for lactase persistence and LAC*R for normal adult lactase restriction. The LAC locus appears to be a regulatory gene that reduces lactase synthesis by reducing the transcription of messenger RNA (Arola and Tamm 1994). Persons inheriting LAC*P from both parents would have lactase persistence into adulthood; those getting LAC*R alleles from both parents would display lactase restriction as adults. Heterozygotes would get different alleles and be LAC*P/LAC*R, but since LAC*P is dominant, lactase activity and ability to digest milk would persist beyond childhood.

Nutritional Implications

As milk and milk products are such rich sources of protein, calcium, carbohydrates, and other nutrients, the nutritional consequences of lactose intolerance in infants and children can be devastating, even lethal, unless other dietary sources are used. Formulas based on soybeans help many youngsters. Adults can get protein from other animal and vegetable sources or from fermented milk products. Yoghurt with live bacterial cultures may be tolerated well. Calcium can be obtained from dark green vegetables or from the bones of small sardines or anchovies consumed whole (Kretchmer 1993). It has been suggested that low milk consumption in elderly lactose intolerance adults might contribute to osteoporosis (Wheadon et al. 1991), but this has not been demonstrated. Lactose-free dairy products and oral lactase preparations are commercially available and help many people enjoy and gain the nutritional benefits of ice cream and other milk-based foods (Ramirez, Lee, and Graham 1994).

Lactase persistence is uncommon in Africans, Asians, southern Europeans, and the indigenous populations of the Americas and the Pacific. Questions have arisen concerning the use of milk as food for children. The American Academy of Pediatrics (AAP), noting the high nutritional value of milk for growing children, has determined that almost all U. S. children under 10, regardless of family background, can digest reasonable quantities of milk. The AAP recommends that the school-lunch half pint (about 240 milliliters [ml]) of milk be supplied to children up to this age, and notes that intolerance to 240 ml is rare even among older teens (American Academy of Pediatrics 1978). Similar results have been reported for African children in South African orphanages (Wittenberg and Moosa 1991). Malnourished African children, such as famine victims, also tolerate up to 350 ml of milk well, which allows the use of this valuable source of nutrients in emergency situations (O’Keefe, Young, and Rund 1990).

Testing for Lactase Persistence

Clinical diagnosis and population surveys for lactose digestion capabilities present several challenges. Clinical symptoms are discovered by self-reporting; thus, double-blind studies, in which neither the experimenter nor the subject knows if a challenge dose contains lactose or a placebo, are most useful. Direct lactase assay using biopsy specimens of intestinal mucosa is obviously an expensive and invasive method, practical only in particular clinical cases. Indirect assays require subjects to fast for several hours before being given doses of lactose in solution.

Then various tests are used to measure the splitting and subsequent metabolism of the disaccharide. Many of the older methods are cumbersome and imprecise. Blood samples may be tested for glucose before lactose challenge and at intervals afterward. High blood glucose levels after lactose ingestion indicate that lactose is being split in the intestine. A variant of this method is to measure blood galactose. Since the liver metabolizes galactose, a dose of ethanol is given shortly before the experimental lactose to inhibit liver action. Another approach is to measure hydrogen gas excreted through the lungs. Subjects who cannot digest lactose will have hydrogen produced by colonic bacteria. Respiratory hydrogen can be conveniently and efficiently measured by gas chromatography. The ethanol-galactose and hydrogen methods are considered the most reliable; the hydrogen technique is cheaper, easier, and noninvasive (Flatz 1987).

Not only must the population studies of lactase activity be methodologically correct, the subjects must also be truly representative of their populations. Studies done on very small numbers of subjects or on hospital patients or other special groups may be unrepresentative. Indeed, some older studies may be unreliable due to poor techniques or sampling problems. Intermarriage and genetic interchange also complicate analysis of the distribution of lactase persistence. Nonetheless, there has been great interest in the geographical and ethnic distribution of adult lactase persistence and the evolution of this unusual phenotype.

Distribution of Lactase Persistence

Several authors have compiled the results of regional studies (Flatz 1987; Kretchmer 1993; Sahi 1994). Some of the major findings are summarized here in Table IV.E.6.1.

It should be noted that data for northern India and Pakistan are suspect and that figures for Finno-Ugrian groups in northern Russia and western Siberia (Khanty, Mansi, Mari, Mordva, Nentsy) are based on small, possibly unrepresentative, samples and older methods (Valenkevich and Yakhontova 1991; Kozlov, Sheremeteva, and Kondik 1992). There is little hard information for the Balkan or Iberian peninsulas, Slavic territories east of Poland, Siberia, central Asia, or the Indian subcontinent. It would also be interesting to have more data on East African pastoralists, such as the Maasai, and on Baggara Arab and other cattle-keeping groups of the West African Sahel.

A high proportion of lactase persisters was noted in northwestern Europe in the early 1970s, and there were similar reports from northern India, from Bedouin and other pastoral populations in the Middle East and northern Africa, and from the Tutsi pastoralists of the Uganda-Rwanda region of East Africa. Very low rates were found among eastern, and most southern, Asians, most Africans, and native populations of the Americas and the Pacific, and only modest rates were found in southern and eastern Europe. In North and South America, Australia, and New Zealand, adult lactase ability is closely linked to place of origin; for example, white Australians resemble their European counterparts in lactase persistence, whereas Aborigines are almost entirely lactose intolerant. Varying degrees of Spanish and Indian ancestry may explain regional differences in Mexico (Rosado et al. 1994). Similarly, a higher than expected prevalence of lactase persistence among Buryat Mongols of Russia’s Lake Baikal region may be due to gene flow from European Russians (Kozlov et al. 1992).

Adult lactase capability appears to have evolved in two, and possibly three, geographic areas. The case is clearest and best documented for northern Europe, where there are very high percentages around the Baltic and North Seas. High levels of lactase persistence seem closely linked to Germanic and Finnic groups. Scandinavia, northern Germany, and Britain have high levels, as do the Finns and Estonians, the Finnic Izhorians west of St. Petersburg, the Mari of the middle Volga basin, and, to a lesser extent, their more distant relations, the Hungarians.

There is a general north—south gradient in Europe, which is evident within Germany, France, Italy, and perhaps Greece. As noted, more information is needed for Spain, Portugal, and eastern Europe, but there may be something of a west—east gradient in the Slavic lands. Varying frequencies of the LAC*P allele among Lapp groups may be related to differing lengths of historical use of reindeer and cow’s milk and to admixture with other Scandinavians (Sahi 1994).

The second center of adult lactase persistence lies in the arid lands of Arabia, the Sahara, and eastern Sudan. There, lactase persistence characterizes only nomadic populations heavily dependent on camels and cattle, such as the Bedouin Arabs, the Tuareg of the Sahara, the Fulani of the West African Sahel, and the Beja and Kabbabish of Sudan. Lower rates among Nigerian Fulani may indicate a higher degree of genetic mixing with other peoples than among the Fulani of Senegal. In contrast, surrounding urban and agricultural populations, whether Arab, Turkish, Iranian, or African, have very low rates. It is interesting to note that the Somali sample also had a low frequency of the LAC*P allele. Possibly, pastoral Somali have higher prevalences than their urban compatriots.

A third center of adult lactase persistence has been suggested among the Tutsi population of the Uganda-Rwanda area of the East African interior. The Tutsi are an aristocratic cattle-herding caste of Nilotic descent who have traditionally ruled over agricultural Bantu-speakers. Table IV.E.6.1 shows that only 7 percent of a sample of 65 Tutsi adults were lactase deficient, but the data are old, there certainly has been some mixture with Bantu-speakers, and the study should be replicated. The Nilotic peoples of the southern Sudan, whence the Tutsi originated a few centuries ago, do not display this trait. Unless the Tutsi result can be confirmed, and the Maasai and other East African Nilotic groups can be tested, this third center of the LAC*P allele must be considered doubtful. If it does exist, it probably arose as a fairly recent mutation, as there are no obvious historical mechanisms to account for gene flow between the Tutsi and desert dwellers farther north.

Evolution of Lactase Persistence

Frederick J. Simoons (1969, 1970) has advanced the thesis that lactase persistence is closely linked to dairying. His culture-evolution hypothesis is that groups that kept cattle and other milk animals would gain a selective advantage if adults retained the ability to use milk and milk products as food.
A mutation like LAC*P would be nutritionally beneficial, and the growing number of milk-using adults would then be encouraged to devote more effort toward livestock raising. In general, the distribution of adult lactase persistence and dairy ing shows a positive relationship. In areas with
no dairying tradition, such as China, Oceania, Pre-Columbian America, or tropical Africa, few adults can digest lactose.

Northern Europe presents the opposite case. More data around the periphery of the two postulated centers would be highly desirable, and we know little about most of the stock-raising societies of central Asia. Still, although the correspondence is not perfect, and gene flow through population mixing complicates the picture, the association seems strong. Given the origins of cattle keeping about 4000 to 3500 B.C. in northern Europe, and even earlier in the Middle East, there probably has been enough time for modest selective pressures to have produced observed LAC*P rates (Sahi 1994).

Other selective forces may also have been at work. Flatz (1987) has suggested that calcium absorption was such a factor in northern Europe. Lactose is known to facilitate calcium absorption in the intestine. The cold, cloudy climate frequently discouraged skin exposure to sunlight, thereby reducing the body’s production of vitamin D. Relatively little dietary vitamin D was available, and so in its absence, calcium was poorly absorbed. Northern populations were thus vulnerable to rickets and osteomalacia. Pelvic deformities made births more difficult. The gradual extinction of the Greenland Viking colony is an example; skeletal evidence shows that such bone diseases were common among this moribund population. A mutant LAC*P allele would not only allow adults to use an excellent source of calcium, but the lactose would also facilitate its absorption. While not proven, this hypothesis has attracted much attention. It would complement the theory that the pale skin of northern Europeans is a genetic trait maximizing the utility of sunlight in vitamin D production and, hence, calcium absorption.

Similarly, other selective pressures facilitating the survival of mutant LAC*P alleles have been postulated for the Sahara—Arabian Peninsula desert region. There is a high degree of dependency on milk among many groups of desert pastoralists, and so a positive link between lactase persistence and milking seems very plausible. In addition, it has been argued (Cook 1978) that the simple fact that milk is a liquid would give adults who could consume it in large quantities a powerful selective advantage. The theory, while unproven, certainly seems plausible. G. C. Cook’s suggestion that lactase persistence conveyed some resistance to gastrointestinal diseases has attracted much less support. At least for cholera, his claim must be rejected, based on what we know of the historical geography of the disease. Cholera seems to have been restricted to the Indian subcontinent until very recent times.

Finally, it seems most likely that the European and Arabia-Sahara centers of LAC*P prevalence, and the Uganda-Rwanda center (if it in fact exists), arose independently. Population movement and gene flow can be very extensive and, no doubt, have played a substantial role around the centers. Despite the efforts of some authors to find a common origin in the ancient Middle East, it is simpler to suggest independent origins than to postulate gene flow from the Middle East to Scandinavia and to the interior of East Africa. The problem might be resolved in the future if gene sequencing could show that the LAC*P alleles in Sweden and Saudi Arabia are, in fact, the same or are distinct forms of the gene with a similar function.

Conclusions

Lactose malabsorption is the normal condition of most adults. Many suffer the clinical symptoms of lactose intolerance if they consume milk, especially in large amounts. In two, or possibly three, places, genetic mutations have arisen that allow adults to gain the nutritional and culinary benefits of milk and many other dairy products. This ability has evolved along with cultural developments with profound implications for livelihood, including, in the northern European case, the development of mixed farming. East Asian, African, Oceanic, and Amerindian peoples, of course, thrived without this genetic trait and its cultural consequences. Their infants and young children enjoyed the nutritional advantages of milk; adults ate other things, including fermented milk products. Milk can be consumed by most lactose-intolerant older children in moderate amounts, and so milk can be a valuable nutrient for the undernourished or famine stricken. Modern commercial lactase products allow most lactose-intolerant adults to consume dairy products; thus, pizza and ice cream need not be forbidden foods.

Finally, the LAC*P and LAC*R genes are interesting far beyond their biomedical significance. Along with linguistics, archaeology, and physical anthropology, further research on lactase genes and other genetic markers will provide clues to the prehistory of peoples, their migrations and interminglings, and the origins and development of major language families.

K. David Patterson

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