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FOOD INTOLERANCE | Lactose Intolerance
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Reintroduction of cows’-milk protein may be performed in 3–6-month intervals after the age of 1 year; with infants having severe CMA, pediatric advice should be sought before attempting reintroduction. Education of both the affected child and parents is vital to successful management of CMA. Both the physician and dietitian can provide guidance and recommend ways for introducing foods in childhood. This helps guarantee a cows’-milk protein-free diet as well as a nutritionally complete diet. Dietitians are also very useful in teaching how to read labels on food packages and identifying milk-derived products. See also: Food Intolerance: Types; Food Allergies; Lactose Intolerance; Elimination Diets; Infant Foods: Milk Formulas
Further Reading American Academy of Pediatrics Committee on Nutrition (2000) Hypoallergenic infant formulas. Pediatrics 106: 346–349. Exl B-M, Mu¨ ller-Teicher G and Vandenplas Y (2000) Preventative possibilities within the context of cow’s milk allergy. Allergy and Clinical Immunology International 12: 68–76. Hosking CS, Heine RG and Hill DJ (2000) The Melbourne milk allergy study – two decades of clinical research. Allergy and Clinical Immunology International 12: 198–205. Novembre E and Vierucci A (2001) Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy 56(suppl. 67): 105–108. Pelto L, Salminen S, Lilius E-M, Nuutila J and Isolauri E (1998) Milk hypersensitivity – key to poorly defined gastrointestinal symptoms in adults. Allergy 53: 307–310. Savilahti E, Kuitunen P and Visakorpi JK (1981) Cow’s milk allergy. In: Lebenthal E (ed.) Textbook of Gastroenterology and Nutrition in Infancy, pp. 689–708. New York: Raven Press. Sicherer SH (2000) Determinants of systemic manifestations of food allergy. Journal of Allergy and Clinical Immunology 106: S251–S257. Sprikkelman AB, Heymans HS and Van Aslderen WMC (2000) Development of allergic disorders in children with cow’s milk allergy or intolerance in infancy. Clinical and Experimental Allergy 30: 1358–1363. Wal J-M (1998) Cow’s milk allergens. Allergy 53: 1013–1022. Zeiger RS (2000) Dietary aspects of food allergy prevention in infants and children. Journal of Pediatric Gastroenterology and Nutrition 30: S77–S86.
Lactose Intolerance F Suarez, Abbott Laboratories, Columbus, OH, USA C Shannon, The Toledo Hospital, Toledo, OH, USA S Hertzler, The Ohio State University, Columbus, OH, USA D Savaiano, Purdue University, West Lafayette, IN, USA Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Introduction Lactose intolerance is best defined as the development of gastrointestinal symptoms after the consumption of the ‘milk sugar’ lactose. Symptoms of intolerance can occur in most humans and all mammals if the amount of lactose consumed exceeds the ability of the gastrointestinal tract to digest this lactose. Thus, lactose intolerance is intermittent since it depends on both the dose of lactose and the response of the gastrointestinal tract. Lactose, a carbohydrate unique to milks and dairy foods, is a disaccharide composed of glucose and galactose, synthesized in the mammary glands of almost all mammals. Young mammals have a large capacity to digest lactose due to a very high activity of a digestive enzyme (a lactase) found on the lining of the small intestine. Most humans and all mammals exhibit a reduced level of this lactase enzyme (and thus a reduced capacity to digest lactose) as they mature past infancy. Interestingly, approximately 25% of the human population maintains a high level of lactase activity and therefore a large capacity to digest lactose throughout life. These individuals are called lactose-tolerant or lactose digesters. A more scientific name for this group is lactase-persistent since the enzyme activity is maintained or persists. The majority of lactose digesters come from northern European, central African and Middle Eastern backgrounds. The remaining 75% of the world’s population, including almost all Asians, Native Americans, and many Africans and Latinos, are thus described as lactose-intolerant or lactase-nonpersistent. The regulation of intestinal lactase activity is under genetic control. The belief that lactase-nonpersistent individuals will always have abdominal symptoms, such as flatulence, abdominal pain, and diarrhea, following dairy food consumption has resulted in many individuals eliminating dairy products from their diet in an effort to prevent symptoms. However, dairy products provide key nutrients and the majority of calcium found in the food supply. The elimination of milk and milk products from the diet makes it very difficult to obtain the recommended dietary allowance of calcium from natural dietary sources. The average American
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woman consumes only 50–60% of the 1000–1500 mg recommended for maximum retention of body calcium. Inadequate calcium intake compromises bone structure and may eventually result in osteoporosis. Thus, it is important to provide clear dietary management that allows lactase-nonpersistent individuals to consume adequate amounts of essential nutrients, including calcium, while avoiding symptoms of intolerance. Lactose intolerance must not be confused with milk allergy. Milk allergy is caused when the immune system reacts against one or more of the proteins found in milk. Milk allergy usually develops in early infancy, before 1 year of age. In developed countries, the incidence in infancy is estimated at 5% and the remission rate is about 90% before 3 years of age. Gastrointestinal symptoms are reported in approximately 50% of infants with milk allergy while cutaneous symptoms are more common and respiratory symptoms less so. In contrast, lactose intolerance has no immunological bases, only follows the loss of intestinal lactase activity, which occurs around 3–5 years of age, and is limited to gastrointestinal symptoms. To understand the dietary management of lactose intolerance, it is important to recognize that multiple factors affect the body’s ability to digest and tolerate lactose. These factors include: (1) the amount of lactose ingested; (2) the level of the residual lactase activity that remains after maturation; (3) gastrointestinal transit time; and (4) the capacity of the colonic microflora to ferment (digest) lactose. This article will review these factors in order to describe a dietary approach to eliminate symptoms of intolerance while consuming adequate calcium, as well as to correct the perception that lactose intolerance is a frequent and severe problem.
Lactose Digestion and Lactase Activity 0005
Lactose is present in varying degrees in all mammalian milk, with the exception of the milk of the sea lion. Mammary glands have a unique capability to synthesize lactose via the enzyme lactose synthetase. Lactose sythetase links the two monosaccharides (simple sugars) glucose and galactose by a beta 1–4 bond, forming the disaccharide lactose. Cows’ milk contains about 50 g l1 of lactose, whereas human milk contains one of the highest concentrations, up to 75 g l1. Table 1 lists the lactose content of common dairy foods. Fluid milk products have the highest concentration of lactose. When cheese is manufactured, lactose remains with the whey. Thus, hard cheeses contain very small amounts of lactose since the whey is removed in the elaboration process.
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Lactose may also be found in medications in biologically insignificant amounts (milligrams) due to its excellent tablet-forming properties. Dietary lactose cannot be absorbed intact directly across the small intestinal mucosa; it must first be hydrolyzed. The enzyme lactase-phlorizin hydrolase (commonly called lactase), a disaccharidase located on the brush border of the intestinal epithelium, breaks the chemical bond between glucose and galactose. These monosaccharides are absorbed across the intestine and transported to the liver for utilization. The lactase enzyme is found must abundantly in the proximal ileum and specifically only hydrolyzes lactose. Human infant lactase is the last of the disaccharidases to appear during fetal production. The gene responsible for the synthesis of lactase has been located in humans on chromosome 2. Lactase activity can be detected as early as 8 weeks after conception and increases to that of only one-third of a full-term infant by 34 weeks’ gestation. During late gestation (35–38 weeks), lactase activity reaches approximately three-quarters of that of a full-term infant. Lactase synthesis and activity are high in nearly all full-term infants and remain high throughout the first 4 years of life. At some point after weaning, a genetically programmed reduction of lactase synthesis occurs, in approximately three-fourths of the world’s population, to a residual level of 5–10% that of infancy. This loss of intestinal lactase activity is not a disease, but rather a normal pattern in human physiology and is transmitted by a recessive gene. The decline in lactase activity is known as lactasenonpersistence (LNP) or primary acquired hypolactasia and cannot be modified by continued exposure to milk or lactose. In humans there appears to be a mosaic pattern of lactase activity in the jejunal enterocytes. In LNP individuals, some jejunal enterocytes produce high amounts of lactase while others, even those sharing the same villus, do not produce lactase. Thus, rather than a uniform reduction in lactase production among all enterocytes, a hypolactasic individual may have a patchy distribution of lactose-producing enterocytes that are low in number relative to the nonlactase-producing enterocytes. Current evidence suggests that the regulation of lactase is accomplished primarily at the level of transcription, although posttranscriptional factors may still be elucidated. Congenital lactose intolerance is an extremely rare inborn error in metabolism in which detectable levels of lactase are absent at birth (0–10 IU g1 protein) and remain abnormal throughout life. An infant with congenital lactase deficiency will have severe diarrheal illness beginning a few days after birth.
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2636 FOOD INTOLERANCE/Lactose Intolerance tbl0001
Table 1 Lactose and calcium content of selected milks, milk products, and substitutes Product
Serving size
Lactose (g per serving)
Calcium (mg)
Milk Low-fat milk, 2% fat Lactaid milk, 1% fat, 70% lactose-reduced Skim milk Chocolate milk Sweetened, condensed whole milk Dried whole milk Nonfat dry milk, instant Buttermilk, fluid Whipped-cream topping Light cream Half and half Low-fat yogurts Cheese Blue Camembert Cheddar Colby Cream Gouda Limburger Parmesan, grated Cheese, pasteurized, processed American Pimento Swiss Cottage cheese Cottage cheese, low-fat, 2% fat Butter Oleomargarine Ice cream Vanilla, regular French, soft Ice milk, vanilla Sherbet, orange Ice, orange
1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (306 g) 1 c (128 g) 1.5 c (91 g) 1 c (245 g) 1 tbs (3 g) 1 tbs (15 g) 1 tbs (15 g) 1 c (227–258 g)
11 9–13 3.6 12–14 10–12 35 48 46 9–11 0.4 0.6 0.6 11–15
291 297 300 302 280 868 1168 1120 285 10 14 16 314–415
1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g)
0.7 0.1 0.4–0.6 0.7 0.8 0.6 0.1 0.8
150 110 204 194 23 198 141 390
1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 c (210 g) 1 c (226 g) 2 pats (10 g) 2 pats (10 g)
0.5 0.5–1.7 0.4–0.6 5–6 7–8 0.1 0
174 174 219 126 155 2 1
1 c (133 g) 1 c (173 g) 1 c (131 g) 1 c (193 g) 100 g
9 9 10 4 0
176 226 176 103 0
c, cup; tbs, tablespoon.
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Treatment with a lactose-free diet eliminates symptoms and promotes normal growth and development. Because lactase enzyme protrudes from the membrane of the epithelial cell and the greatest activity is found at the tip of the intestinal villi, lactase is extremely vulnerable to intestinal disease or insult. Secondary hypolactasia is a temporary condition caused by damage to the enterocytes via disease, poisons such as alcohol, medications, surgery, or radiation to the gastrointestinal tract (Table 2). This condition is relatively common in developing countries, but most common in Third-World countries where chronic intestinal infections are prevalent. Once the causative disease is resolved and the epithelium heals, lactase activity returns to normal. Total resolution of the insufficiency may require up to 6 months or more of diet therapy.
Assessment of Lactase Levels and Lactose Maldigestion Lactase level can be ascertained with a modest degree of accuracy simply from the determination of the subject’s heritage, because prevalence varies among ethnic and racial groups (Table 3). Individuals of African, Asian, middle Eastern, Mediterranean (Jews, southern Italians, Greeks, Arabs), and Native American origin have a greater than 70% chance of being LNP. Subjects of Scandinavian and middle European origin have about a 5% and 15% chance of being LNP, respectively. The geographical and racial distribution of lactase persistence has led to the hypothesis that three separate gene mutations occurred several thousands of years ago in places where dairy foods had become
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Table 2 Potential causes of secondary hypolactasia Diseases Small-bowel HIV enteropathy Regional enteritis (e.g., Crohn’s disease) Sprue (celiac and tropical) Whipple’s disease (intestinal lipodystrophy) Ascaris lumbricoides infection Blind-loop syndrome Giardiasis Infectious diarrhea Short gut Iatrogenic Chemotherapy Radiation enteritis Surgical resection of intestine Medications Colchicine (antigout) Neomycin (antibiotic) Kanamycin (antibiotic) Aminosalicylic acid (antibiotic)
Multisystem Carcinoid syndrome Cystic fibrosis Diabetic gastropathy Protein-energy malnutrition Zollinger–Ellison syndrome Alcoholism Iron deficiency
Adapted from: Srinivasan R and Minocha A (1998) When to suspect lactose intolerance: symptomatic, ethnic, and laboratory issues. Postgraduate Medicine (1988) 104: 109–123; Scrimshaw NS and Murray EB (1988) The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. American Journal of Clinical Nutrition 48: 1083–1159; Savaiano DA and Levitt MD (1987) Milk intolerance and microbe-containing dairy foods. Journal of Dairy Science 70: 397–406. HIV, human immunodeficiency virus.
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an important component of the adult diet. Darwinian theory suggests that mutation yielded a survival advantage to subjects provided they were drinking milk. Herding animals and the use of mammalian milk as a human food originated in northern Europe, the Middle East, and central Africa several thousand years ago. Interestingly, it is in these populations that lactase persistence also appeared. Thus, the current view is that selective advantage in these populations led to the maintenance of a genetic mutation in each of these three populations. Inheritance has spread the persistence trait to other populations. Table 4 shows that approximately 200 million individuals in the USA are lactase-persistent. Lactase levels can be measured directly or indirectly. Directly assaying the lactase activity requires a mucosal biopsy from the jejunum, since the enzyme is attached to the brush border of the small intestinal mucosa. Such biopsies can be obtained at endoscopies or via the use of a variety of tubes equipped with biopsy capsules. While this test can accurately measure lactase activity, it is an expensive, invasive, and time-consuming test and is therefore rarely used clinically. Thus, lactase activity is usually assessed indirectly from measurements of lactose absorption via blood or breath tests. Digested lactose results in free glucose, which is absorbed rapidly, and ultimately
Table 3 Projections of lactose maldigestion around the world (in millions) Area
Africa Asia Europe Latin America North America Oceania World
% Lactose maldigesters (LM)
1990 Population
LM
2000 Population
LM
2020 Population
LM
75 100 20 70 25 25
629 3186 721 442 278 27 5283
472 3186 144 309 70 7 4188 (79%)
805 3688 729 520 307 31 6080
604 3688 146 364 77 8 4887 (80%)
1172 4578 722 645 363 38 7518
879 4578 144 452 91 10 6154 (82%)
GeoHive, 2002 ONLINE. Available http://www.geohive.com/global/index.php [2002].
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Table 4 Projections of lactose maldigestion in the USA (in millions)
African-Americans Asian-Americans Caucasian Hispanic (all races) Native Americans Total (% of population)
% Lactose maldigesters (LM)
1990 millions of people
LM millions of people
2000 millions of people
LM millions of people
2025 millions of people
LM millions of people
75 100 20 60 100 29
30 7 188 22 2 249
23 7 28 13 2 72 29%
34 11 197 31 2 275
25.5 11 39.4 18.6 2 96.5 35%
44 20.5 209 60 2.5 336
33 20.5 41.8 36 2.5 133.8 40%
Source: US Department of Commerce; 1990 census and estimates.
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increases blood glucose levels. The blood glucose test involves feeding a standard 50-g lactose dose and measurement of plasma glucose every 30 min over a period of 2 h. In the presence of lactose maldigestion, blood glucose increases less than 25 mg dl1 above the fasting level. Unfortunately, this test is mildly invasive and with a relatively low reliability. Because of its ease, low cost, and noninvasiveness, the breath hydrogen test is most widely used to diagnose lactose maldigestion. Undigested lactose remains in the intestine and is fermented by colonic bacteria, producing hydrogen gas, carbon dioxide, and methane in some individuals. Bacterial fermentation is the only source of molecular hydrogen in the body. A portion of the hydrogen produced in the colon diffuses into the blood and is excreted via the lungs. The breath test measures the excretion of this hydrogen. Typically, a subject is given an oral dose of lactose following an overnight ( 12 h) fast. Breath samples are collected at regular intervals for a period of 5–8 h and analyzed by gas chromatography. The historical test used 50 g of lactose as a challenge dose, and an increase of 20 parts per million (p.p.m.) or greater above the fasting level as an indicator of lactose maldigestion. More recently, it has been shown that using a sum of hydrogen from hours 5, 6, and 7 and a 15 p.p.m. above-fasting criterion for maldigestion resulted in 100% sensitivity and specificity for carbohydrate maldigestion.
Pathophysiology of Lactose Maldigestion 0015
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A positive breath hydrogen test measures undigested carbohydrate in the colon and is indicative of lactose maldigestion. However, the correlation between lactose maldigestion and intolerance symptoms, such as flatulence, abdominal pain, and diarrhea, is unclear. The lactose may or may not result in perceptible symptoms depending on a number of factors, including the amount of lactose entering the colon, the metabolic activity of the colonic flora, the absorptive capacity of the colonic mucosa for the end products of lactose fermentation, and the ‘irritability’ of the colon. Colonic bacteria metabolize lactose, thereby reducing osmotic pressure in the colon. If the colonic bacteria did not ferment undigested lactose, the osmotic activity of even relatively small doses of lactose could result in diarrhea. However, diarrhea is virtually never encountered when LNP subjects ingest a cup of milk (12 g of lactose). Colonic bacteria ferment lactose to short-chain fatty acids that are readily absorbed by the colon. However, when massive quantities of carbohydrate are maldigested, colonic absorption of fatty acids may not keep up with
production. In this situation the bacteria may actually enhance the osmotic activity and hence aggravate the ensuing diarrhea. In the fermentation process of lactose, appreciable quantities of gas (carbon dioxide, hydrogen, and sometimes methane) are also produced. The removal of these gases is accomplished by bacterial utilization, excretion in flatus, or by absorption through the colon. With small doses of lactose, gas may be removed as rapidly as it is produced and there will be no symptoms. However, with large lactose loads these removal mechanisms may not keep up with production, and bloating, distention, and flatulence result. A final important factor that plays a role in the development of gastrointestinal symptoms is the response of the colon to the presence of gas and organic acids. Subjects with an ‘irritable’ colon might perceive symptoms whereas subject with a ‘nonirritable’ colon might tolerate the same degree of distention without symptoms. The intensity of symptoms may also vary with the amount of lactose consumed, the degree of colonic adaptation, and the physical form of the lactose-containing food.
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The Relationship Between Lactose Maldigestion and Lactose Intolerance The larger the dose of lactose, the greater the risk that the LNP subject will perceive symptoms of lactose intolerance. Early unblinded studies in which subjects were fed milk or lactose and then asked if they had symptoms suggested that over 45% had symptoms following a glass of milk or its lactose equivalent (12 g). The results of such studies have provided the basis for claims that many subjects require a diet severely restricted in milk and milk products or the use of a variety of commercially available lactosedigestive aids. However, tolerance to milk can be affected by factors unrelated to its lactose content and may be due to psychological factors or cultural attitudes toward milk. There is a psychogenic component to abdominal symptomatology, particularly relating to the minor and nonspecific type of symptoms (bloating, distension), that may result from ingested food. The true symptomatic potential of milk (or other foods) can only be obtained with rigidly controlled double-blind studies. Under these controlled conditions, researchers have found that lactose intolerance is less prevalent than commonly believed. For example, in a well-controlled trial, 50 g of lactose (the quantity in a quart (approx. 1l) of milk), taken as a single dose caused symptoms in most of LNP subjects. On the other hand, several blinded studies indicated that LNP subjects tolerated
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up to one cup (237 ml) of milk without experiencing significant symptoms. However, the results of these studies did not gain general acceptance, in part because of failure to utilize subjects with ‘severe’ lactose intolerance. Some LNP individuals believe that small amounts of lactose, such as the amount used with coffee or cereal, cause gastrointestinal distress. In 1995, our group conducted a study in 30 selfdescribed ‘severely lactose-intolerant individuals.’ Initial breath hydrogen test measurements indicated that approximately 30% (9 of 30) of the subjects claiming severe lactose intolerance were digesters, and thus, had no physiological basis for intolerance symptoms. Among the true lactose maldigesters there were no significant differences in symptoms of bloating, flatulence, or number of flatus passages during the period when conventional milk (lactosecontaining) versus lactose-hydrolyzed milk was ingested. During both treatment periods, symptoms were extremely mild. The triviality of these symptoms with conventional (or lactose-hydrolyzed) milk was particularly impressive given the subjects’ prestudy perception that symptoms would be so bad that they would be compelled to withdraw from the study. These findings further demonstrate how strongly behavioral and psychological factors influence symptom reporting. Additional research is necessary to evaluate the psychological component of symptom reporting in lactose maldigesters.
Lactose Digestion and Calcium 0021
Lactose maldigestion could potentially increase risk of osteoporosis either by decreased milk, and therefore calcium, intake or by decreased calcium absorption. Lactose maldigestion has been associated with lower calcium intakes and consequently a higher prevalence of osteoporosis. A sizable fraction of lactose maldigesters may unnecessarily restrict their intake of lactose-containing, calcium-rich dairy foods. Milk and milk products contribute 73% of the calcium to the US food. A second potential relationship between lactose maldigestion and osteoporosis is that maldigestion of lactose decreases absorption of calcium. Human and animal studies suggest that lactose stimulates the intestinal absorption of calcium. However, there is considerable disagreement regarding the influence of lactose and lactose maldigestion on calcium absorption in adults. Differences in study methodology (milk versus water, dose of lactose, and the choice of method for determining calcium absorption) may explain contrasting results. Physiologic doses of lactose (up to two cups (474 ml) of milk) do not appear to have a significant impact on calcium absorption. Therefore, increased prevalence
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of osteoporosis in lactose maldigesters is most likely related to avoidance of dairy foods and subsequently inadequate calcium intake rather than impaired intestinal calcium absorption.
Dietary Management for Lactose Maldigestion There are several dietary strategies that effectively reduce or eliminate intolerance symptoms without compromising nutritional status (Table 5).
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Dose–Response to Lactose
There is a strong positive correlation between the dose of lactose consumed and the symptomatic response. In general, increasing the amount of lactose consumed increases the number and severity of symptoms. In lactose maldigesters, 2 g of lactose is almost completely absorbed, whereas 6 g of lactose results in a minimal degree of maldigestion as measured by breath hydrogen. On average, maldigesters absorbed about half of a 12.5-g lactose load, whereas the other half passes to the terminal ileum. Interestingly, unblinded studies have frequently reported intolerance symptoms after consuming only 12 g lactose. In 1995 a double-blind protocol demonstrated that feeding 12 g of lactose (approximately one cup of milk) with a meal resulted in minimal to no symptoms in maldigesters who believed themselves to be extremely intolerant to lactose. Further evidence indicated that lactose-intolerant individuals could consume two cups (474 ml) of milk daily with divided doses at breakfast and dinner, without experiencing appreciable symptoms. Overall, a dose containing 18–25 g of lactose has the potential to produce symptoms (mostly flatulence) in approximately half of a population. However, the frequency of symptoms varies from less than 40% to greater than 90% of a subgroup. Thus, a first important dietary strategy is to limit milk consumption to one eight-ounce glass (12.5 g lactose) per meal. Doing so will dramatically reduce the likelihood of intolerance symptoms.
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Factors Affecting Gastrointestinal Transit of Lactose
A key explanation of the large variability in dose– response studies is whether or not the lactose is fed with a meal. Consuming milk with other foods slows the intestinal transit of lactose. Slowing the intestinal transit permits longer contact between residual lactase in the small intestine and lactose, thus improving digestion and reducing the potential for symptoms. It is also possible that additional food in the intestine may slow the rate at which lactose is delivery
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2640 FOOD INTOLERANCE/Lactose Intolerance tbl0005
Table 5 Dietary strategies for lactose intolerance Factors affecting lactose digestion
Dietary strategy
References
Dose of lactose
Consume a cup (237 ml) of milk or less at a time, containing up to 12 g lactose
Intestinal transit
Consume milk with other foods, rather than alone, to slow the intestinal transit of lactose
Yogurts
Consume yogurts containing active bacteria cultures. A serving, or even more, should be well tolerated. Lactose in yogurts is better digested than the lactose in milks Pasteurized yogurts do not improve lactose digestion. However, these products, when consumed, produce little to no symptoms Over-the-counter lactase supplement pills, capsules, and drops may be used when large doses of lactose (> 12 g) are consumed at once Lactose-hydrolyzed milks are also well tolerated
Suarez et al. 1995 Hertzler et al. 1996 Suarez and Savaiano 1997 Solomons et al. 1985 Martini and Savaiano 1988 Dehkordi et al. 1995 Kolars et al. 1984 Gilliland and Kim 1984 Savaiano et al. 1984 Shermak et al. 1995 Savaiano et al. 1984 Kolars et al. 1984 Gilliland and Kim 1984 Moskovitz et al. 1987 Lin et al. 1993 Ramirez et al. 1994
Digestive aids
Colon adaptation
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Consume lactose-containing foods daily to increase the colon bacteria’s ability to metabolize undigested lactose
Nielsen et al. 1984 Biller et al. 1987 Rosado et al. 1988 Brand et al. 1991 Perman et al. 1981 Florent et al. 1985 Hertzler et al. 1996
in the colon. A slower entry of lactose into the colon might also improve the fermentation and reduce the potential for symptoms. Individual foods also affect lactose digestion and tolerance. Whole milk, due to its greater fat and energy content, may slightly decrease breath hydrogen relative to skim milk. Whether this effect is large enough to improve tolerance is unclear. Likewise, the addition of chocolate to milk may improve lactose digestion and symptoms, possibly due to its higher osmolality or energy content and/or the effect of cocoa on intestinal transit. Thus, a second key dietary recommendation is to consume milk and other lactose-containing dairy foods with meals. This strategy will also insure that adequate calcium intake can be achieved without symptoms of intolerance.
activity of b-galactosidase. This activity functions during the manufacturing process, and most importantly also during gastrointestinal digestion of lactose in vivo in the stomach and/or small intestine. Clinical studies have showed that consumption of up to 18 g lactose as yogurt (two cups of yogurt) is well tolerated, and results in few symptoms of intolerance. Pasteurization of yogurt increases the shelf-life but decreases the number of active cultures that are partly responsible for improved lactose digestion. However, pasteurized yogurt is moderately well tolerated, producing minimal symptoms. It is believed that the physical form of the yogurt and the caloric density are additional factors that improve tolerance to lactose found in yogurt. Thus, a third dietary strategy is to include yogurts as a part of a calcium-rich and well-tolerated diet.
Yogurts
Lactase Supplements and Lactose-Reduced Milks
Lactose that is found in yogurt with live active cultures (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarius subsp. thermophilus) is digested better than lactose in milk. As a result, yogurt is well tolerated by lactose-intolerant individuals. During the manufacture of yogurts, milk solids are typically added to fluid milk to enhance the product. During yogurt production, the bacteria reduce the lactose level from around 6% to approximately 4%. Lactic acid bacteria in yogurt exhibit a very high
Pills, capsules, and drops that contain lactase derived from yeast (Kluyveromyces lactis) or fungal (Aspergillus niger, A. oryzae) sources have proved effective for lactose digestion. Since 1984, these over-the-counter preparations have been given the status of generally recognized as safe (GRAS) by the US Food and Drug Administration. Additionally, milk that has been treated with lactase, resulting in a 70–100% reduction in lactose, is commercially available. Lactose-hydrolyzed milk typically has increased
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Unfermented Acidophilus Milk 0029
Various strains of Lactobacillus acidophilus exist; however strain NCFM (North Carolina Food Microbiology) has been most extensively studied and used in commercial products. Unfermented acidophilus milk tastes identical to unaltered milk since the NCFM strain does not multiply in the product, provided that the storage temperature is below 40 F (5 C). L. acidophilus strain NCFM is derived from human fecal samples and contains b-galactosidase (lactase). However unfermented acidophilus milk does not enhance lactose digestion or reduce intolerance symptoms in doses present in commercially available products. It appears that the ingested bacteria are not disrupted by the bile acids, thus microbial lactase is not released. However, when acidophilus milk is sonicated, which destroys the bacteria membrane, lactose digestion improves. Colonic Fermentation and Bacterial Adaptation of Lactose
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The colonic bacteria ferment undigested lactose and produce short-chain fatty acids and gases. Historically, this fermentation process was viewed as a cause of lactose-intolerance symptoms. However, it is now recognized that the fermentation of lactose, as well as other nonabsorbed carbohydrates plays an important role in the health of the colon, and impacts the nutritional status of the individual. The most compelling evidence for colonic bacterial adaptation to lactose comes from studies where the amount of lactose is carefully controlled and gradually increased over time. Increasing the daily lactose dose from 0.3 g kg1 body weight up to 1.0 g kg1 body weight over a period of several days to 3 weeks results in a several-fold increase in fecal b-galactosidase activity. This elevated enzyme activity returns to baseline levels with in a few days after the lactose-feeding period. Furthermore, lactose feeding dramatically decreases the breath hydrogen response to a lactose challenge dose (Figure 1). In fact, after lactose
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∆ Breath hydrogen (p.p.m.)
sweetness, due to the presence of free glucose. Lactose hydrolysis can be carried out by the consumer at home, or products can be purchased already in lowlactose form. A number of studies have evaluated the effectiveness of these products. Doses of 3000–6000 FCC (Food Chemical Codex) units of lactase administered just prior to milk consumption decrease both breath hydrogen and symptom responses to lactose loads ranging from 17 to 20 g. Thus, a fourth strategy is to include lactose-reduced products and/or utilize enzyme preparations if symptoms of intolerance are present, despite adherence to simpler and more costeffective approaches.
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4 5 Time (h)
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Figure 1 Breath hydrogen response to a lactose challenge after lactose (open squares) or dextrose (filled squares) feeding periods. Data are the means + SEM, n ¼ 20. Reproduced from Hertzler SR and Savaiano DA. Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. American Journal of Clinical Nutrition 64: 232–236, with permission.
adaptation, the subjects may no longer appear to be lactose maldigesters according to the breath hydrogen test. The large doses of lactose fed during these adaptation periods (up to 70 g day1) result in only minor symptoms. Additionally, the severity and frequency of flatus symptoms in response to the lactose challenge dose are significantly reduced. Thus it appears that colonic bacterial adaptation to lactose does occur. Although the mechanisms that cause colonic adaptation need further investigation, it is clear that many lactose-intolerant individuals will develop a tolerance to milk if they consume it regularly. This may represent a simpler and less expensive solution than the use of lactose digestive aids. Thus, a final dietary recommendation to lactose-intolerant individuals is not to avoid dairy foods, but rather to include them in the diet on a daily basis. Daily consumption of milk and dairy foods will enhance colon bacterial adaptation and reduce the likelihood for symptoms of intolerance.
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Conclusion Milk and milk products are important sources of many nutrients, including calcium. The avoidance of dairy products to prevent intolerance symptoms jeopardizes bone density, thus increasing the risk for osteoporosis. The inescapable conclusion to be drawn from blinded studies is that virtually all LNP subjects, including even those with severe self-perceived intolerance, can drink milk or milk
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2642 FOOD INTOLERANCE/Elimination Diets
products with minimal symptoms if taken in single serving doses with meals. Thus, the role of the health care provider is to convince the patient with selfdiagnosed or, less commonly, physician-diagnosed lactose intolerance that various dietary strategies effectively manage lactose intolerance by reducing or eliminating gastrointestinal symptoms. However, beliefs concerning lactose intolerance are not easily reversed, and it may be very difficult to convince patients that their abdominal symptoms are not appreciably aggravated by ingestion of moderate doses of lactose. See also: Food Intolerance: Milk Allergy; Inborn Errors of Metabolism: Overview; Lactic Acid Bacteria; Lactose; Yogurt: The Product and its Manufacture; Yogurt-based Products; Dietary Importance
Further Readings Biller JA, King S, Rosenthal A and Grand RJ (1987) Efficacy of lactase-treated milk for lactose-intolerant pediatric patients. Journal of Pediatrics 111: 91–94. Dehkordi N, Rao DR, Warren AP and Chawan CB (1995) Lactose malabsorption as influenced by chocolate milk, skim milk, sucrose, whole milk, and lactic cultures. Journal of the American Dietary Association 95: 484– 486. Florent C, Flourie B, Leblond A, Rautureau M, Bernier JJ and Rambaud JC (1985) Influence of chronic lactulose ingestion on the colonic metabolism of lactulose in man (an in vivo study). Journal of Clinical Investment 75: 608–613. Gilliland SE and Kim HS (1984) Effect of viable starter culture bacteria in yogurt on lactose utilization in humans. Journal of Dairy Science 67: 1–6. Hertzler SR and Savaiano DA (1996) Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. American Journal of Clinical Nutrition 64: 232–236. Kolars JC, Levitt MD, Aouji M and Savaiano DA (1984) Yogurt – an autodigesting source of lactose. New England Journal of Medicine 310: 1–3. Lin M, Dipalma JA, Martini MC, Gross J, Harlander SK and Savaiano DA (1993) Comparative effects of exogenous lactase (B-galactosidase) preparations on in vivo lactose digestion. Digestive Diseases and Sciences 38: 2022–2027. Martini MC and Savaiano DA (1988) Reduced intolerance symptoms from lactose consumed during a meal. American Journal of Clinical Nutrition 47: 57–60. Moskovitz M, Curtis C and Gavaler J (1987) Does oral enzyme replacement therapy reverse intestinal lactose malabsorption? American Journal of Gastroenterology 82: 632–635. Nielsen OH, Schiotz PO, Rasmussen SN and Krasilnikoff PA (1984) Calcium absorption and acceptance of low-lactose milk among children with primary lactase
deficiency. Journal of Pediatric Gastroenterology and Nutrition 3: 219–223. Perman JA, Modler S and Olson AC (1981) Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora. Studies in vivo and in vitro. Journal of Clinical Investment 67: 643–650. Ramirez FC, Lee K and Graham DY (1994) All lactase preparations are not the same: results of a prospective, randomized, placebo-controlled trial. American Journal of Gastroenterology 89: 566–570. Rosado JL, Morales M, Pasquetti A, Nobara R and Hernandez L (1988) Nutritional evaluation of a lactose-hydrolyzed milk-based enteral formula diet. I. A comparative study of carbohydrate digestion and clinical tolerance. Rev Invest Clin 40: 141–147. Savaiano DA, AbouElAnouar A, Smith DE and Levitt MD (1984) Lactose malabsorption from yogurt, pasteurized yogurt, sweet acidophilus milk, and cultured milk in lactase-deficient individuals. American Journal of Clinical Nutrition 40: 1219–1223. Shermak MA, Saavedra JM, Jackson TL, Huang SS, Bayless TM and Perman JA (1995) Effect of yogurt on symptoms and kinetics of hydrogen production in lactosemalabsorbing children. American Journal of Clinical Nutrition 62: 1003–1006. Solomons NW, Guerrero AM and Torun B (1985) Dietary manipulation of postprandial colonic lactose fermentation: I. Effect of solid foods in a meal. American Journal of Clinical Nutrition 41: 199–208. Suarez FL and Savaiano DA (1994) Lactose digestion and tolerance in adult and elderly Asian-Americans. American Journal of Clinical Nutrition 59: 1021–1024.
Elimination Diets C M Carter, Great Ormond Street Hospital for Children, London, UK Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Definitions and Aims An elimination diet is one which excludes one or more foods or food additives. The aim of an elimination diet is to diagnose and/or treat food-allergic disease. Food-allergic disease is an intolerance to food(s) resulting from an abnormal immunological response. The title ‘food allergy and intolerance’ is often used because an immunological basis cannot always be demonstrated. This article discusses the indications for the use of an elimination diet and the dietary manipulations involved.
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Indications and Contraindications The symptoms of food allergy or intolerance may come on quickly or slowly (Table 1). Symptoms may
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Reintroduction of cows’-milk protein may be performed in 3–6-month intervals after the age of 1 year; with infants having severe CMA, pediatric advice should be sought before attempting reintroduction. Education of both the affected child and parents is vital to successful management of CMA. Both the physician and dietitian can provide guidance and recommend ways for introducing foods in childhood. This helps guarantee a cows’-milk protein-free diet as well as a nutritionally complete diet. Dietitians are also very useful in teaching how to read labels on food packages and identifying milk-derived products. See also: Food Intolerance: Types; Food Allergies; Lactose Intolerance; Elimination Diets; Infant Foods: Milk Formulas
Further Reading American Academy of Pediatrics Committee on Nutrition (2000) Hypoallergenic infant formulas. Pediatrics 106: 346–349. Exl B-M, Mu¨ ller-Teicher G and Vandenplas Y (2000) Preventative possibilities within the context of cow’s milk allergy. Allergy and Clinical Immunology International 12: 68–76. Hosking CS, Heine RG and Hill DJ (2000) The Melbourne milk allergy study – two decades of clinical research. Allergy and Clinical Immunology International 12: 198–205. Novembre E and Vierucci A (2001) Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy 56(suppl. 67): 105–108. Pelto L, Salminen S, Lilius E-M, Nuutila J and Isolauri E (1998) Milk hypersensitivity – key to poorly defined gastrointestinal symptoms in adults. Allergy 53: 307–310. Savilahti E, Kuitunen P and Visakorpi JK (1981) Cow’s milk allergy. In: Lebenthal E (ed.) Textbook of Gastroenterology and Nutrition in Infancy, pp. 689–708. New York: Raven Press. Sicherer SH (2000) Determinants of systemic manifestations of food allergy. Journal of Allergy and Clinical Immunology 106: S251–S257. Sprikkelman AB, Heymans HS and Van Aslderen WMC (2000) Development of allergic disorders in children with cow’s milk allergy or intolerance in infancy. Clinical and Experimental Allergy 30: 1358–1363. Wal J-M (1998) Cow’s milk allergens. Allergy 53: 1013–1022. Zeiger RS (2000) Dietary aspects of food allergy prevention in infants and children. Journal of Pediatric Gastroenterology and Nutrition 30: S77–S86.
Lactose Intolerance F Suarez, Abbott Laboratories, Columbus, OH, USA C Shannon, The Toledo Hospital, Toledo, OH, USA S Hertzler, The Ohio State University, Columbus, OH, USA D Savaiano, Purdue University, West Lafayette, IN, USA Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Introduction Lactose intolerance is best defined as the development of gastrointestinal symptoms after the consumption of the ‘milk sugar’ lactose. Symptoms of intolerance can occur in most humans and all mammals if the amount of lactose consumed exceeds the ability of the gastrointestinal tract to digest this lactose. Thus, lactose intolerance is intermittent since it depends on both the dose of lactose and the response of the gastrointestinal tract. Lactose, a carbohydrate unique to milks and dairy foods, is a disaccharide composed of glucose and galactose, synthesized in the mammary glands of almost all mammals. Young mammals have a large capacity to digest lactose due to a very high activity of a digestive enzyme (a lactase) found on the lining of the small intestine. Most humans and all mammals exhibit a reduced level of this lactase enzyme (and thus a reduced capacity to digest lactose) as they mature past infancy. Interestingly, approximately 25% of the human population maintains a high level of lactase activity and therefore a large capacity to digest lactose throughout life. These individuals are called lactose-tolerant or lactose digesters. A more scientific name for this group is lactase-persistent since the enzyme activity is maintained or persists. The majority of lactose digesters come from northern European, central African and Middle Eastern backgrounds. The remaining 75% of the world’s population, including almost all Asians, Native Americans, and many Africans and Latinos, are thus described as lactose-intolerant or lactase-nonpersistent. The regulation of intestinal lactase activity is under genetic control. The belief that lactase-nonpersistent individuals will always have abdominal symptoms, such as flatulence, abdominal pain, and diarrhea, following dairy food consumption has resulted in many individuals eliminating dairy products from their diet in an effort to prevent symptoms. However, dairy products provide key nutrients and the majority of calcium found in the food supply. The elimination of milk and milk products from the diet makes it very difficult to obtain the recommended dietary allowance of calcium from natural dietary sources. The average American
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FOOD INTOLERANCE/Lactose Intolerance
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woman consumes only 50–60% of the 1000–1500 mg recommended for maximum retention of body calcium. Inadequate calcium intake compromises bone structure and may eventually result in osteoporosis. Thus, it is important to provide clear dietary management that allows lactase-nonpersistent individuals to consume adequate amounts of essential nutrients, including calcium, while avoiding symptoms of intolerance. Lactose intolerance must not be confused with milk allergy. Milk allergy is caused when the immune system reacts against one or more of the proteins found in milk. Milk allergy usually develops in early infancy, before 1 year of age. In developed countries, the incidence in infancy is estimated at 5% and the remission rate is about 90% before 3 years of age. Gastrointestinal symptoms are reported in approximately 50% of infants with milk allergy while cutaneous symptoms are more common and respiratory symptoms less so. In contrast, lactose intolerance has no immunological bases, only follows the loss of intestinal lactase activity, which occurs around 3–5 years of age, and is limited to gastrointestinal symptoms. To understand the dietary management of lactose intolerance, it is important to recognize that multiple factors affect the body’s ability to digest and tolerate lactose. These factors include: (1) the amount of lactose ingested; (2) the level of the residual lactase activity that remains after maturation; (3) gastrointestinal transit time; and (4) the capacity of the colonic microflora to ferment (digest) lactose. This article will review these factors in order to describe a dietary approach to eliminate symptoms of intolerance while consuming adequate calcium, as well as to correct the perception that lactose intolerance is a frequent and severe problem.
Lactose Digestion and Lactase Activity 0005
Lactose is present in varying degrees in all mammalian milk, with the exception of the milk of the sea lion. Mammary glands have a unique capability to synthesize lactose via the enzyme lactose synthetase. Lactose sythetase links the two monosaccharides (simple sugars) glucose and galactose by a beta 1–4 bond, forming the disaccharide lactose. Cows’ milk contains about 50 g l1 of lactose, whereas human milk contains one of the highest concentrations, up to 75 g l1. Table 1 lists the lactose content of common dairy foods. Fluid milk products have the highest concentration of lactose. When cheese is manufactured, lactose remains with the whey. Thus, hard cheeses contain very small amounts of lactose since the whey is removed in the elaboration process.
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Lactose may also be found in medications in biologically insignificant amounts (milligrams) due to its excellent tablet-forming properties. Dietary lactose cannot be absorbed intact directly across the small intestinal mucosa; it must first be hydrolyzed. The enzyme lactase-phlorizin hydrolase (commonly called lactase), a disaccharidase located on the brush border of the intestinal epithelium, breaks the chemical bond between glucose and galactose. These monosaccharides are absorbed across the intestine and transported to the liver for utilization. The lactase enzyme is found must abundantly in the proximal ileum and specifically only hydrolyzes lactose. Human infant lactase is the last of the disaccharidases to appear during fetal production. The gene responsible for the synthesis of lactase has been located in humans on chromosome 2. Lactase activity can be detected as early as 8 weeks after conception and increases to that of only one-third of a full-term infant by 34 weeks’ gestation. During late gestation (35–38 weeks), lactase activity reaches approximately three-quarters of that of a full-term infant. Lactase synthesis and activity are high in nearly all full-term infants and remain high throughout the first 4 years of life. At some point after weaning, a genetically programmed reduction of lactase synthesis occurs, in approximately three-fourths of the world’s population, to a residual level of 5–10% that of infancy. This loss of intestinal lactase activity is not a disease, but rather a normal pattern in human physiology and is transmitted by a recessive gene. The decline in lactase activity is known as lactasenonpersistence (LNP) or primary acquired hypolactasia and cannot be modified by continued exposure to milk or lactose. In humans there appears to be a mosaic pattern of lactase activity in the jejunal enterocytes. In LNP individuals, some jejunal enterocytes produce high amounts of lactase while others, even those sharing the same villus, do not produce lactase. Thus, rather than a uniform reduction in lactase production among all enterocytes, a hypolactasic individual may have a patchy distribution of lactose-producing enterocytes that are low in number relative to the nonlactase-producing enterocytes. Current evidence suggests that the regulation of lactase is accomplished primarily at the level of transcription, although posttranscriptional factors may still be elucidated. Congenital lactose intolerance is an extremely rare inborn error in metabolism in which detectable levels of lactase are absent at birth (0–10 IU g1 protein) and remain abnormal throughout life. An infant with congenital lactase deficiency will have severe diarrheal illness beginning a few days after birth.
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2636 FOOD INTOLERANCE/Lactose Intolerance tbl0001
Table 1 Lactose and calcium content of selected milks, milk products, and substitutes Product
Serving size
Lactose (g per serving)
Calcium (mg)
Milk Low-fat milk, 2% fat Lactaid milk, 1% fat, 70% lactose-reduced Skim milk Chocolate milk Sweetened, condensed whole milk Dried whole milk Nonfat dry milk, instant Buttermilk, fluid Whipped-cream topping Light cream Half and half Low-fat yogurts Cheese Blue Camembert Cheddar Colby Cream Gouda Limburger Parmesan, grated Cheese, pasteurized, processed American Pimento Swiss Cottage cheese Cottage cheese, low-fat, 2% fat Butter Oleomargarine Ice cream Vanilla, regular French, soft Ice milk, vanilla Sherbet, orange Ice, orange
1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (237 g) 1 c (306 g) 1 c (128 g) 1.5 c (91 g) 1 c (245 g) 1 tbs (3 g) 1 tbs (15 g) 1 tbs (15 g) 1 c (227–258 g)
11 9–13 3.6 12–14 10–12 35 48 46 9–11 0.4 0.6 0.6 11–15
291 297 300 302 280 868 1168 1120 285 10 14 16 314–415
1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 oz (28 g)
0.7 0.1 0.4–0.6 0.7 0.8 0.6 0.1 0.8
150 110 204 194 23 198 141 390
1 oz (28 g) 1 oz (28 g) 1 oz (28 g) 1 c (210 g) 1 c (226 g) 2 pats (10 g) 2 pats (10 g)
0.5 0.5–1.7 0.4–0.6 5–6 7–8 0.1 0
174 174 219 126 155 2 1
1 c (133 g) 1 c (173 g) 1 c (131 g) 1 c (193 g) 100 g
9 9 10 4 0
176 226 176 103 0
c, cup; tbs, tablespoon.
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Treatment with a lactose-free diet eliminates symptoms and promotes normal growth and development. Because lactase enzyme protrudes from the membrane of the epithelial cell and the greatest activity is found at the tip of the intestinal villi, lactase is extremely vulnerable to intestinal disease or insult. Secondary hypolactasia is a temporary condition caused by damage to the enterocytes via disease, poisons such as alcohol, medications, surgery, or radiation to the gastrointestinal tract (Table 2). This condition is relatively common in developing countries, but most common in Third-World countries where chronic intestinal infections are prevalent. Once the causative disease is resolved and the epithelium heals, lactase activity returns to normal. Total resolution of the insufficiency may require up to 6 months or more of diet therapy.
Assessment of Lactase Levels and Lactose Maldigestion Lactase level can be ascertained with a modest degree of accuracy simply from the determination of the subject’s heritage, because prevalence varies among ethnic and racial groups (Table 3). Individuals of African, Asian, middle Eastern, Mediterranean (Jews, southern Italians, Greeks, Arabs), and Native American origin have a greater than 70% chance of being LNP. Subjects of Scandinavian and middle European origin have about a 5% and 15% chance of being LNP, respectively. The geographical and racial distribution of lactase persistence has led to the hypothesis that three separate gene mutations occurred several thousands of years ago in places where dairy foods had become
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FOOD INTOLERANCE/Lactose Intolerance tbl0002
Table 2 Potential causes of secondary hypolactasia Diseases Small-bowel HIV enteropathy Regional enteritis (e.g., Crohn’s disease) Sprue (celiac and tropical) Whipple’s disease (intestinal lipodystrophy) Ascaris lumbricoides infection Blind-loop syndrome Giardiasis Infectious diarrhea Short gut Iatrogenic Chemotherapy Radiation enteritis Surgical resection of intestine Medications Colchicine (antigout) Neomycin (antibiotic) Kanamycin (antibiotic) Aminosalicylic acid (antibiotic)
Multisystem Carcinoid syndrome Cystic fibrosis Diabetic gastropathy Protein-energy malnutrition Zollinger–Ellison syndrome Alcoholism Iron deficiency
Adapted from: Srinivasan R and Minocha A (1998) When to suspect lactose intolerance: symptomatic, ethnic, and laboratory issues. Postgraduate Medicine (1988) 104: 109–123; Scrimshaw NS and Murray EB (1988) The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. American Journal of Clinical Nutrition 48: 1083–1159; Savaiano DA and Levitt MD (1987) Milk intolerance and microbe-containing dairy foods. Journal of Dairy Science 70: 397–406. HIV, human immunodeficiency virus.
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an important component of the adult diet. Darwinian theory suggests that mutation yielded a survival advantage to subjects provided they were drinking milk. Herding animals and the use of mammalian milk as a human food originated in northern Europe, the Middle East, and central Africa several thousand years ago. Interestingly, it is in these populations that lactase persistence also appeared. Thus, the current view is that selective advantage in these populations led to the maintenance of a genetic mutation in each of these three populations. Inheritance has spread the persistence trait to other populations. Table 4 shows that approximately 200 million individuals in the USA are lactase-persistent. Lactase levels can be measured directly or indirectly. Directly assaying the lactase activity requires a mucosal biopsy from the jejunum, since the enzyme is attached to the brush border of the small intestinal mucosa. Such biopsies can be obtained at endoscopies or via the use of a variety of tubes equipped with biopsy capsules. While this test can accurately measure lactase activity, it is an expensive, invasive, and time-consuming test and is therefore rarely used clinically. Thus, lactase activity is usually assessed indirectly from measurements of lactose absorption via blood or breath tests. Digested lactose results in free glucose, which is absorbed rapidly, and ultimately
Table 3 Projections of lactose maldigestion around the world (in millions) Area
Africa Asia Europe Latin America North America Oceania World
% Lactose maldigesters (LM)
1990 Population
LM
2000 Population
LM
2020 Population
LM
75 100 20 70 25 25
629 3186 721 442 278 27 5283
472 3186 144 309 70 7 4188 (79%)
805 3688 729 520 307 31 6080
604 3688 146 364 77 8 4887 (80%)
1172 4578 722 645 363 38 7518
879 4578 144 452 91 10 6154 (82%)
GeoHive, 2002 ONLINE. Available http://www.geohive.com/global/index.php [2002].
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Table 4 Projections of lactose maldigestion in the USA (in millions)
African-Americans Asian-Americans Caucasian Hispanic (all races) Native Americans Total (% of population)
% Lactose maldigesters (LM)
1990 millions of people
LM millions of people
2000 millions of people
LM millions of people
2025 millions of people
LM millions of people
75 100 20 60 100 29
30 7 188 22 2 249
23 7 28 13 2 72 29%
34 11 197 31 2 275
25.5 11 39.4 18.6 2 96.5 35%
44 20.5 209 60 2.5 336
33 20.5 41.8 36 2.5 133.8 40%
Source: US Department of Commerce; 1990 census and estimates.
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increases blood glucose levels. The blood glucose test involves feeding a standard 50-g lactose dose and measurement of plasma glucose every 30 min over a period of 2 h. In the presence of lactose maldigestion, blood glucose increases less than 25 mg dl1 above the fasting level. Unfortunately, this test is mildly invasive and with a relatively low reliability. Because of its ease, low cost, and noninvasiveness, the breath hydrogen test is most widely used to diagnose lactose maldigestion. Undigested lactose remains in the intestine and is fermented by colonic bacteria, producing hydrogen gas, carbon dioxide, and methane in some individuals. Bacterial fermentation is the only source of molecular hydrogen in the body. A portion of the hydrogen produced in the colon diffuses into the blood and is excreted via the lungs. The breath test measures the excretion of this hydrogen. Typically, a subject is given an oral dose of lactose following an overnight ( 12 h) fast. Breath samples are collected at regular intervals for a period of 5–8 h and analyzed by gas chromatography. The historical test used 50 g of lactose as a challenge dose, and an increase of 20 parts per million (p.p.m.) or greater above the fasting level as an indicator of lactose maldigestion. More recently, it has been shown that using a sum of hydrogen from hours 5, 6, and 7 and a 15 p.p.m. above-fasting criterion for maldigestion resulted in 100% sensitivity and specificity for carbohydrate maldigestion.
Pathophysiology of Lactose Maldigestion 0015
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A positive breath hydrogen test measures undigested carbohydrate in the colon and is indicative of lactose maldigestion. However, the correlation between lactose maldigestion and intolerance symptoms, such as flatulence, abdominal pain, and diarrhea, is unclear. The lactose may or may not result in perceptible symptoms depending on a number of factors, including the amount of lactose entering the colon, the metabolic activity of the colonic flora, the absorptive capacity of the colonic mucosa for the end products of lactose fermentation, and the ‘irritability’ of the colon. Colonic bacteria metabolize lactose, thereby reducing osmotic pressure in the colon. If the colonic bacteria did not ferment undigested lactose, the osmotic activity of even relatively small doses of lactose could result in diarrhea. However, diarrhea is virtually never encountered when LNP subjects ingest a cup of milk (12 g of lactose). Colonic bacteria ferment lactose to short-chain fatty acids that are readily absorbed by the colon. However, when massive quantities of carbohydrate are maldigested, colonic absorption of fatty acids may not keep up with
production. In this situation the bacteria may actually enhance the osmotic activity and hence aggravate the ensuing diarrhea. In the fermentation process of lactose, appreciable quantities of gas (carbon dioxide, hydrogen, and sometimes methane) are also produced. The removal of these gases is accomplished by bacterial utilization, excretion in flatus, or by absorption through the colon. With small doses of lactose, gas may be removed as rapidly as it is produced and there will be no symptoms. However, with large lactose loads these removal mechanisms may not keep up with production, and bloating, distention, and flatulence result. A final important factor that plays a role in the development of gastrointestinal symptoms is the response of the colon to the presence of gas and organic acids. Subjects with an ‘irritable’ colon might perceive symptoms whereas subject with a ‘nonirritable’ colon might tolerate the same degree of distention without symptoms. The intensity of symptoms may also vary with the amount of lactose consumed, the degree of colonic adaptation, and the physical form of the lactose-containing food.
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The Relationship Between Lactose Maldigestion and Lactose Intolerance The larger the dose of lactose, the greater the risk that the LNP subject will perceive symptoms of lactose intolerance. Early unblinded studies in which subjects were fed milk or lactose and then asked if they had symptoms suggested that over 45% had symptoms following a glass of milk or its lactose equivalent (12 g). The results of such studies have provided the basis for claims that many subjects require a diet severely restricted in milk and milk products or the use of a variety of commercially available lactosedigestive aids. However, tolerance to milk can be affected by factors unrelated to its lactose content and may be due to psychological factors or cultural attitudes toward milk. There is a psychogenic component to abdominal symptomatology, particularly relating to the minor and nonspecific type of symptoms (bloating, distension), that may result from ingested food. The true symptomatic potential of milk (or other foods) can only be obtained with rigidly controlled double-blind studies. Under these controlled conditions, researchers have found that lactose intolerance is less prevalent than commonly believed. For example, in a well-controlled trial, 50 g of lactose (the quantity in a quart (approx. 1l) of milk), taken as a single dose caused symptoms in most of LNP subjects. On the other hand, several blinded studies indicated that LNP subjects tolerated
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up to one cup (237 ml) of milk without experiencing significant symptoms. However, the results of these studies did not gain general acceptance, in part because of failure to utilize subjects with ‘severe’ lactose intolerance. Some LNP individuals believe that small amounts of lactose, such as the amount used with coffee or cereal, cause gastrointestinal distress. In 1995, our group conducted a study in 30 selfdescribed ‘severely lactose-intolerant individuals.’ Initial breath hydrogen test measurements indicated that approximately 30% (9 of 30) of the subjects claiming severe lactose intolerance were digesters, and thus, had no physiological basis for intolerance symptoms. Among the true lactose maldigesters there were no significant differences in symptoms of bloating, flatulence, or number of flatus passages during the period when conventional milk (lactosecontaining) versus lactose-hydrolyzed milk was ingested. During both treatment periods, symptoms were extremely mild. The triviality of these symptoms with conventional (or lactose-hydrolyzed) milk was particularly impressive given the subjects’ prestudy perception that symptoms would be so bad that they would be compelled to withdraw from the study. These findings further demonstrate how strongly behavioral and psychological factors influence symptom reporting. Additional research is necessary to evaluate the psychological component of symptom reporting in lactose maldigesters.
Lactose Digestion and Calcium 0021
Lactose maldigestion could potentially increase risk of osteoporosis either by decreased milk, and therefore calcium, intake or by decreased calcium absorption. Lactose maldigestion has been associated with lower calcium intakes and consequently a higher prevalence of osteoporosis. A sizable fraction of lactose maldigesters may unnecessarily restrict their intake of lactose-containing, calcium-rich dairy foods. Milk and milk products contribute 73% of the calcium to the US food. A second potential relationship between lactose maldigestion and osteoporosis is that maldigestion of lactose decreases absorption of calcium. Human and animal studies suggest that lactose stimulates the intestinal absorption of calcium. However, there is considerable disagreement regarding the influence of lactose and lactose maldigestion on calcium absorption in adults. Differences in study methodology (milk versus water, dose of lactose, and the choice of method for determining calcium absorption) may explain contrasting results. Physiologic doses of lactose (up to two cups (474 ml) of milk) do not appear to have a significant impact on calcium absorption. Therefore, increased prevalence
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of osteoporosis in lactose maldigesters is most likely related to avoidance of dairy foods and subsequently inadequate calcium intake rather than impaired intestinal calcium absorption.
Dietary Management for Lactose Maldigestion There are several dietary strategies that effectively reduce or eliminate intolerance symptoms without compromising nutritional status (Table 5).
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Dose–Response to Lactose
There is a strong positive correlation between the dose of lactose consumed and the symptomatic response. In general, increasing the amount of lactose consumed increases the number and severity of symptoms. In lactose maldigesters, 2 g of lactose is almost completely absorbed, whereas 6 g of lactose results in a minimal degree of maldigestion as measured by breath hydrogen. On average, maldigesters absorbed about half of a 12.5-g lactose load, whereas the other half passes to the terminal ileum. Interestingly, unblinded studies have frequently reported intolerance symptoms after consuming only 12 g lactose. In 1995 a double-blind protocol demonstrated that feeding 12 g of lactose (approximately one cup of milk) with a meal resulted in minimal to no symptoms in maldigesters who believed themselves to be extremely intolerant to lactose. Further evidence indicated that lactose-intolerant individuals could consume two cups (474 ml) of milk daily with divided doses at breakfast and dinner, without experiencing appreciable symptoms. Overall, a dose containing 18–25 g of lactose has the potential to produce symptoms (mostly flatulence) in approximately half of a population. However, the frequency of symptoms varies from less than 40% to greater than 90% of a subgroup. Thus, a first important dietary strategy is to limit milk consumption to one eight-ounce glass (12.5 g lactose) per meal. Doing so will dramatically reduce the likelihood of intolerance symptoms.
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Factors Affecting Gastrointestinal Transit of Lactose
A key explanation of the large variability in dose– response studies is whether or not the lactose is fed with a meal. Consuming milk with other foods slows the intestinal transit of lactose. Slowing the intestinal transit permits longer contact between residual lactase in the small intestine and lactose, thus improving digestion and reducing the potential for symptoms. It is also possible that additional food in the intestine may slow the rate at which lactose is delivery
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2640 FOOD INTOLERANCE/Lactose Intolerance tbl0005
Table 5 Dietary strategies for lactose intolerance Factors affecting lactose digestion
Dietary strategy
References
Dose of lactose
Consume a cup (237 ml) of milk or less at a time, containing up to 12 g lactose
Intestinal transit
Consume milk with other foods, rather than alone, to slow the intestinal transit of lactose
Yogurts
Consume yogurts containing active bacteria cultures. A serving, or even more, should be well tolerated. Lactose in yogurts is better digested than the lactose in milks Pasteurized yogurts do not improve lactose digestion. However, these products, when consumed, produce little to no symptoms Over-the-counter lactase supplement pills, capsules, and drops may be used when large doses of lactose (> 12 g) are consumed at once Lactose-hydrolyzed milks are also well tolerated
Suarez et al. 1995 Hertzler et al. 1996 Suarez and Savaiano 1997 Solomons et al. 1985 Martini and Savaiano 1988 Dehkordi et al. 1995 Kolars et al. 1984 Gilliland and Kim 1984 Savaiano et al. 1984 Shermak et al. 1995 Savaiano et al. 1984 Kolars et al. 1984 Gilliland and Kim 1984 Moskovitz et al. 1987 Lin et al. 1993 Ramirez et al. 1994
Digestive aids
Colon adaptation
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Consume lactose-containing foods daily to increase the colon bacteria’s ability to metabolize undigested lactose
Nielsen et al. 1984 Biller et al. 1987 Rosado et al. 1988 Brand et al. 1991 Perman et al. 1981 Florent et al. 1985 Hertzler et al. 1996
in the colon. A slower entry of lactose into the colon might also improve the fermentation and reduce the potential for symptoms. Individual foods also affect lactose digestion and tolerance. Whole milk, due to its greater fat and energy content, may slightly decrease breath hydrogen relative to skim milk. Whether this effect is large enough to improve tolerance is unclear. Likewise, the addition of chocolate to milk may improve lactose digestion and symptoms, possibly due to its higher osmolality or energy content and/or the effect of cocoa on intestinal transit. Thus, a second key dietary recommendation is to consume milk and other lactose-containing dairy foods with meals. This strategy will also insure that adequate calcium intake can be achieved without symptoms of intolerance.
activity of b-galactosidase. This activity functions during the manufacturing process, and most importantly also during gastrointestinal digestion of lactose in vivo in the stomach and/or small intestine. Clinical studies have showed that consumption of up to 18 g lactose as yogurt (two cups of yogurt) is well tolerated, and results in few symptoms of intolerance. Pasteurization of yogurt increases the shelf-life but decreases the number of active cultures that are partly responsible for improved lactose digestion. However, pasteurized yogurt is moderately well tolerated, producing minimal symptoms. It is believed that the physical form of the yogurt and the caloric density are additional factors that improve tolerance to lactose found in yogurt. Thus, a third dietary strategy is to include yogurts as a part of a calcium-rich and well-tolerated diet.
Yogurts
Lactase Supplements and Lactose-Reduced Milks
Lactose that is found in yogurt with live active cultures (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarius subsp. thermophilus) is digested better than lactose in milk. As a result, yogurt is well tolerated by lactose-intolerant individuals. During the manufacture of yogurts, milk solids are typically added to fluid milk to enhance the product. During yogurt production, the bacteria reduce the lactose level from around 6% to approximately 4%. Lactic acid bacteria in yogurt exhibit a very high
Pills, capsules, and drops that contain lactase derived from yeast (Kluyveromyces lactis) or fungal (Aspergillus niger, A. oryzae) sources have proved effective for lactose digestion. Since 1984, these over-the-counter preparations have been given the status of generally recognized as safe (GRAS) by the US Food and Drug Administration. Additionally, milk that has been treated with lactase, resulting in a 70–100% reduction in lactose, is commercially available. Lactose-hydrolyzed milk typically has increased
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FOOD INTOLERANCE/Lactose Intolerance
Unfermented Acidophilus Milk 0029
Various strains of Lactobacillus acidophilus exist; however strain NCFM (North Carolina Food Microbiology) has been most extensively studied and used in commercial products. Unfermented acidophilus milk tastes identical to unaltered milk since the NCFM strain does not multiply in the product, provided that the storage temperature is below 40 F (5 C). L. acidophilus strain NCFM is derived from human fecal samples and contains b-galactosidase (lactase). However unfermented acidophilus milk does not enhance lactose digestion or reduce intolerance symptoms in doses present in commercially available products. It appears that the ingested bacteria are not disrupted by the bile acids, thus microbial lactase is not released. However, when acidophilus milk is sonicated, which destroys the bacteria membrane, lactose digestion improves. Colonic Fermentation and Bacterial Adaptation of Lactose
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The colonic bacteria ferment undigested lactose and produce short-chain fatty acids and gases. Historically, this fermentation process was viewed as a cause of lactose-intolerance symptoms. However, it is now recognized that the fermentation of lactose, as well as other nonabsorbed carbohydrates plays an important role in the health of the colon, and impacts the nutritional status of the individual. The most compelling evidence for colonic bacterial adaptation to lactose comes from studies where the amount of lactose is carefully controlled and gradually increased over time. Increasing the daily lactose dose from 0.3 g kg1 body weight up to 1.0 g kg1 body weight over a period of several days to 3 weeks results in a several-fold increase in fecal b-galactosidase activity. This elevated enzyme activity returns to baseline levels with in a few days after the lactose-feeding period. Furthermore, lactose feeding dramatically decreases the breath hydrogen response to a lactose challenge dose (Figure 1). In fact, after lactose
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∆ Breath hydrogen (p.p.m.)
sweetness, due to the presence of free glucose. Lactose hydrolysis can be carried out by the consumer at home, or products can be purchased already in lowlactose form. A number of studies have evaluated the effectiveness of these products. Doses of 3000–6000 FCC (Food Chemical Codex) units of lactase administered just prior to milk consumption decrease both breath hydrogen and symptom responses to lactose loads ranging from 17 to 20 g. Thus, a fourth strategy is to include lactose-reduced products and/or utilize enzyme preparations if symptoms of intolerance are present, despite adherence to simpler and more costeffective approaches.
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Figure 1 Breath hydrogen response to a lactose challenge after lactose (open squares) or dextrose (filled squares) feeding periods. Data are the means + SEM, n ¼ 20. Reproduced from Hertzler SR and Savaiano DA. Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. American Journal of Clinical Nutrition 64: 232–236, with permission.
adaptation, the subjects may no longer appear to be lactose maldigesters according to the breath hydrogen test. The large doses of lactose fed during these adaptation periods (up to 70 g day1) result in only minor symptoms. Additionally, the severity and frequency of flatus symptoms in response to the lactose challenge dose are significantly reduced. Thus it appears that colonic bacterial adaptation to lactose does occur. Although the mechanisms that cause colonic adaptation need further investigation, it is clear that many lactose-intolerant individuals will develop a tolerance to milk if they consume it regularly. This may represent a simpler and less expensive solution than the use of lactose digestive aids. Thus, a final dietary recommendation to lactose-intolerant individuals is not to avoid dairy foods, but rather to include them in the diet on a daily basis. Daily consumption of milk and dairy foods will enhance colon bacterial adaptation and reduce the likelihood for symptoms of intolerance.
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Conclusion Milk and milk products are important sources of many nutrients, including calcium. The avoidance of dairy products to prevent intolerance symptoms jeopardizes bone density, thus increasing the risk for osteoporosis. The inescapable conclusion to be drawn from blinded studies is that virtually all LNP subjects, including even those with severe self-perceived intolerance, can drink milk or milk
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2642 FOOD INTOLERANCE/Elimination Diets
products with minimal symptoms if taken in single serving doses with meals. Thus, the role of the health care provider is to convince the patient with selfdiagnosed or, less commonly, physician-diagnosed lactose intolerance that various dietary strategies effectively manage lactose intolerance by reducing or eliminating gastrointestinal symptoms. However, beliefs concerning lactose intolerance are not easily reversed, and it may be very difficult to convince patients that their abdominal symptoms are not appreciably aggravated by ingestion of moderate doses of lactose. See also: Food Intolerance: Milk Allergy; Inborn Errors of Metabolism: Overview; Lactic Acid Bacteria; Lactose; Yogurt: The Product and its Manufacture; Yogurt-based Products; Dietary Importance
Further Readings Biller JA, King S, Rosenthal A and Grand RJ (1987) Efficacy of lactase-treated milk for lactose-intolerant pediatric patients. Journal of Pediatrics 111: 91–94. Dehkordi N, Rao DR, Warren AP and Chawan CB (1995) Lactose malabsorption as influenced by chocolate milk, skim milk, sucrose, whole milk, and lactic cultures. Journal of the American Dietary Association 95: 484– 486. Florent C, Flourie B, Leblond A, Rautureau M, Bernier JJ and Rambaud JC (1985) Influence of chronic lactulose ingestion on the colonic metabolism of lactulose in man (an in vivo study). Journal of Clinical Investment 75: 608–613. Gilliland SE and Kim HS (1984) Effect of viable starter culture bacteria in yogurt on lactose utilization in humans. Journal of Dairy Science 67: 1–6. Hertzler SR and Savaiano DA (1996) Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. American Journal of Clinical Nutrition 64: 232–236. Kolars JC, Levitt MD, Aouji M and Savaiano DA (1984) Yogurt – an autodigesting source of lactose. New England Journal of Medicine 310: 1–3. Lin M, Dipalma JA, Martini MC, Gross J, Harlander SK and Savaiano DA (1993) Comparative effects of exogenous lactase (B-galactosidase) preparations on in vivo lactose digestion. Digestive Diseases and Sciences 38: 2022–2027. Martini MC and Savaiano DA (1988) Reduced intolerance symptoms from lactose consumed during a meal. American Journal of Clinical Nutrition 47: 57–60. Moskovitz M, Curtis C and Gavaler J (1987) Does oral enzyme replacement therapy reverse intestinal lactose malabsorption? American Journal of Gastroenterology 82: 632–635. Nielsen OH, Schiotz PO, Rasmussen SN and Krasilnikoff PA (1984) Calcium absorption and acceptance of low-lactose milk among children with primary lactase
deficiency. Journal of Pediatric Gastroenterology and Nutrition 3: 219–223. Perman JA, Modler S and Olson AC (1981) Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora. Studies in vivo and in vitro. Journal of Clinical Investment 67: 643–650. Ramirez FC, Lee K and Graham DY (1994) All lactase preparations are not the same: results of a prospective, randomized, placebo-controlled trial. American Journal of Gastroenterology 89: 566–570. Rosado JL, Morales M, Pasquetti A, Nobara R and Hernandez L (1988) Nutritional evaluation of a lactose-hydrolyzed milk-based enteral formula diet. I. A comparative study of carbohydrate digestion and clinical tolerance. Rev Invest Clin 40: 141–147. Savaiano DA, AbouElAnouar A, Smith DE and Levitt MD (1984) Lactose malabsorption from yogurt, pasteurized yogurt, sweet acidophilus milk, and cultured milk in lactase-deficient individuals. American Journal of Clinical Nutrition 40: 1219–1223. Shermak MA, Saavedra JM, Jackson TL, Huang SS, Bayless TM and Perman JA (1995) Effect of yogurt on symptoms and kinetics of hydrogen production in lactosemalabsorbing children. American Journal of Clinical Nutrition 62: 1003–1006. Solomons NW, Guerrero AM and Torun B (1985) Dietary manipulation of postprandial colonic lactose fermentation: I. Effect of solid foods in a meal. American Journal of Clinical Nutrition 41: 199–208. Suarez FL and Savaiano DA (1994) Lactose digestion and tolerance in adult and elderly Asian-Americans. American Journal of Clinical Nutrition 59: 1021–1024.
Elimination Diets C M Carter, Great Ormond Street Hospital for Children, London, UK Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Definitions and Aims An elimination diet is one which excludes one or more foods or food additives. The aim of an elimination diet is to diagnose and/or treat food-allergic disease. Food-allergic disease is an intolerance to food(s) resulting from an abnormal immunological response. The title ‘food allergy and intolerance’ is often used because an immunological basis cannot always be demonstrated. This article discusses the indications for the use of an elimination diet and the dietary manipulations involved.
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Indications and Contraindications The symptoms of food allergy or intolerance may come on quickly or slowly (Table 1). Symptoms may
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