Nutrient Considerations in Lactose Intolerance

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Nutrient Considerations in Lactose Intolerance DENNIS SAVAIANO,1 STEVE HERTZLER,2 KARRY A. JACKSON,1 AND FABRIZIS L. SUAREZ3 Purdue University, West Lafayette, Indiana Ohio State University, Columbus, Ohio 3 Minneapolis Veteran’s Administration Medical Center, Minneapolis, Minnesota 1 2

I. INTRODUCTION

This chapter will (1) review the pathophysiology of lactose maldigestion, (2) attempt to correct common misconceptions concerning the frequency and severity of lactose intolerance symptoms, and (3) provide dietary strategies to minimize symptoms of intolerance.

Ingestion of a large, single dose of lactose (e.g., 50 g, the quantity in a quart of milk) by lactose maldigesters commonly results in diarrhea, bloating, and flatulence [1]. The wide dissemination of this information has led some of the lay population and a fraction of the medical community to attribute common gastrointestinal symptoms to lactose intolerance, independent of the dose of lactose ingested. As a result, a segment of the population avoids dairy products due to the belief that even trivial doses of lactose will induce diarrhea or gas. However, multiple factors affect the ability of lactose to induce perceptible symptoms. These factors include residual lactase activity [2], gastrointestinal transit time [3], lactose consumed with other foods [4], lactose load [5], and colonic fermentation [6]. In the United States, approximately 72 million individuals are lactose maldigesters, many of whom are Asian-Americans, African-Americans, and Hispanics (Table 1). These minority groups are rapidly growing segments of the population. Thus, the overall number of lactose maldigesters will grow in the United States in coming years.

TABLE 1

African-Americans Asian-Americans Caucasian Hispanic (all races) Native Americans Total Percentage lactose maldigesters

II. LACTOSE IN THE DIET Lactose is the primary disaccharide in virtually all mammalian milks. It is unique among the major dietary sugars because of the (␤-1 r 4 linkage between its component monosaccharides, galactose and glucose. Lactose production in nature is limited to the mammalian breast, which contains the enzyme system (lactose synthase) necessary to create this linkage [7]. Human milk contains approximately 7% lactose by weight, which is among the highest lactose concentrations of all mammalian milks [5]. Cow’s milk contains 4–5% lactose. Lactose, being water soluble, is associated with the whey portion of dairy foods. Thus, hard cheeses (with the whey removed from the curds) contain very little lactose compared to fluid milk.

Projections of Lactose Maldigestion in the United States

Percentage lactose maldigesters (LM)

Population 1990 (millions)

75 100 20 60 100 29

30 7 188 22 2 249

LM 1990 (millions) 23 7 37.6 13 2 82.6 33

Population 2000 (millions) 34 11 197 31 2 275

LM 2000 (millions) 25.5 11 39.4 18.6 2 96.5 35

Population 2025 (millions) 44 20.5 209 60 2.5 336

LM 2025 (millions) 33 20.5 41.8 36 2.5 133.8 40

Source: Estimates based on U.S. Department of Commerce, 1990 Census.

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2001 by Academic Press. All rights of reproduction in any form reserved.

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In addition to food sources of lactose, small amounts of lactose are found in a wide variety of medications due to the excellent tablet-forming properties of lactose [5]. However, lactose is usually present in milligram, rather than gram, quantities in most medications and the amount is biologically insignificant.

III. DIGESTION OF LACTOSE The small intestine is normally impermeable to lactose. Lactose must first be hydrolyzed to glucose and galactose, which are subsequently absorbed. Inability to digest lactose is referred to as lactose maldigestion. Lactose digestion is dependent on the enzyme lactase-phlorizin hydrolase (LPH), a microvillar protein that has at least three enzyme activities: galactosidase, phlorizin hydrolase, and glycosylceramidase [8, 9]. Synthesis of LPH occurs in enterocytes, with the highest and most uniform synthesis being in the jejunum in humans [10]. The LPH gene is located on chromosome 2 and directs the synthesis of a pre-proLPH that is processed intracellularly (and possibly by pancreatic proteases) into the mature form that is anchored in the cell membrane at the brush border [11, 12]. Lactase activity develops late in gestation compared to other disaccharidases. Lactase activity in a fetus at 34 weeks is only 30% that of a full-term infant, rising to 70% of the full-term activity by 35–38 weeks [13].

IV. LOSS OF LACTASE ACTIVITY Full-term infants possess high lactase activity, except for congenital lactase deficiency, in which lactase is completely absent at birth. Holzel et al. [14] first described congenital lactase deficiency in 1959. A very rare condition even in Finland (where it is most common), only 42 cases were diagnosed from 1966 to 1998 [11]. Lactase activity in jejunal biopsy specimens from infants with congenital lactase deficiency is reduced to 0–10 IU/g protein, and severe diarrhea results from unabsorbed lactose [11]. Treatment with a lactose-free formula eliminates symptoms and promotes normal growth and development [15]. Primary acquired hypolactasia, in which there is up to a 90–95% reduction in lactase activity, is much more common than congenital lactase deficiency (alactasia) [16]. The preferred term for this type of hypolactasia is lactase nonpersistence (LNP). It is estimated that approximately 75% of the world’s population are LNP (see Table 2), with the exception of Northern Europeans and a few pastoral tribes in Africa and the Middle East that maintain infantile levels of lactase throughout life [17]. Thus, LNP is not a ‘‘lactase deficiency’’ disease, but is the normal pattern in human physiology, similar to the physiology of other mammalian species. This permanent loss of lactase occurs sometime after 3–5 years of age [9, 18]. It is hypothesized that lactase persistence is the

result of a genetic mutation 3000–5000 years ago in populations where dairy foods had become an important component of the adult diet [19]. A gene mutation may have conferred a selective evolutionary advantage in these populations [20]. Lactase persistence is inherited as an autosomal dominant characteristic [17]. The genetic regulation of LPH has been studied extensively. Most evidence supports reduced levels of lactase mRNA in lactose maldigesters, suggesting that regulation is primarily at the level of transcription [21–24]. However, hypolactasia is sometimes present even when lactase mRNA is abundant, suggesting that post-transcriptional factors play a role [10, 25, 26]. One potential reason for conflicting results is the intestinal segment examined (duodenum versus jejunum). Lactase expression is higher and more uniform in the jejunum compared to the duodenum [27, 28]. Another potential discrepancy is the age of the subjects studied. A poor correlation between lactase mRNA and lactase activity was reported in intestinal biopsies from children, although the biopsy specimens in this study were duodenal [26]. Lactase activity in the jejunal enterocytes is found in a ‘‘mosaic’’type pattern [29]. In hypolactasic individuals, some jejunal enterocytes produce high amounts of lactase while others, even those sharing the same villus, do not produce lactase [10]. 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 non-lactase-producing enterocytes. In lactase persistent individuals, all villus enterocytes may produce lactase. Current evidence suggests that the regulation of lactase is accomplished primarily at the level of transcription, although post-transcriptional factors (e.g., degradation of mRNA and post-translational processing of the LPH protein) could be important in some individuals. Secondary hypolactasia occurs as the result of damage to the enterocytes via disease, medications, surgery, or radiation to the gastrointestinal tract (see Table 3) [5, 30, 31]. For example, the prevalence of microsporidiosis, which is associated with hypolactasia, can be as high as 50% in HIVinfected patients [32]. Seventy percent of HIV-infected patients showed evidence of lactose maldigestion compared to only 34% of controls [33]. In addition, the severity of lactose maldigestion increases in the more advanced stages of the disease. In general, secondary hypolactasia is reversible once the underlying cause is treated, but this reversal may require 6 months or more of diet therapy [5].

V. DIAGNOSIS OF LACTOSE MALDIGESTION A. Direct Assessment Methods Lactose digestion can be assessed directly or indirectly. The direct method involves obtaining a biopsy specimen of intes-

CHAPTER 37 TABLE 2

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Projections of Lactose Maldigestion around the World

Percentage lactose maldigesters (LM)

Population 1995 (millions)

75 100 20 70 25 25

Africa Asia Europe Latin America North America Oceania Total Percentage lactose maldigesters

•

753 3299 809 501 286 28 5676

LM 1995 (millions) 565 3299 162 351 72 7 4456 78%

Population 2000 (millions) 877 3543 827 550 297 30 6127

LM 2000 (millions) 658 3543 165 385 74 8 4833 79%

Population 2025 (millions)

LM 2025 (millions)

1642 4466 893 786 347 39 8177

1231 4466 893 786 347 39 6523 80%

Source: Population estimates from the United Nations.

tinal tissue and assaying for lactose activity or by intestinal perfusion studies [34]. While these tests can accurately measure lactase activity, they are invasive and seldom used clinically.

B. Indirect Assessment Methods Several indirect methods for assessing lactose digestion are available, including blood, urine, stool, and breath tests. Blood tests involve feeding a standard 50-g lactose dose and measurement of plasma glucose every 15–30 minutes over a period of 30 minutes to 2 hours. A rise in blood glucose of at least 25–30 mg/dL (1.5–1.7 mmol/L) is indicative of normal lactose digestion [34]. Unfortunately, blood glucose lev-

TABLE 3

els are subject to a variety of hormonal influences, reducing the reliability of this test. A blood test for galactose has been developed to correct this problem. The lactose dose is administered with a 500 mg/kg dose of ethanol (to prevent conversion of galactose to glucose in the liver) [34]. The galactose test is more reliable than the glucose test, but the ethanol exposure and invasive blood sampling are disadvantages. A commonly used urine test involves the measurement of galactose in the urine, rather than the blood, during the lactose tolerance test with ethanol. Another urine test is conducted by simultaneously administering lactose and lactulose (a nonabsorbable disaccharide) [34]. Small amounts of lactose (up to 1% of the ingested dose) and lactulose diffuse unmediated across the intestinal mucosa and are

Potential Causes of Secondary Hypolactasia

Diseases Small bowel

Multisystem

Iatrogenic

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

Carcinoid syndrome Cystic fibrosis Diabetic gastropathy Protein energy malnutrition Zollinger-Ellison syndrome Alcoholism Iron deficiency

Chemotherapy Radiation enteritis Surgical resection of intestine Medications Colchicine (antigout) Neomycin (antibiotic) Kanamycin (antibiotic) Aminosalicylic acid (antibiotic)

Sources: Adapted with permission from: Srinivasan, R., and Minocha, A. (1998). When to suspect lactose intolerance: Symptomatic, ethnic, and laboratory issues. Postgrad. Med. 104(3), 109–123; Scrimshaw, N. S., and Murray, E. B. (1998). The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am. J. Clin. Nutr. 48, 1083–1159; and Savaiano, D. A., and Levitt, M. D. (1987). Milk intolerance and microbe-containing dairy foods. J. Dairy Sci. 70, 397–406.

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excreted in the urine. The ratio of lactose to lactulose in the urine (collected over 10 hours) is determined by the hydrolysis of lactose. A value of less than 0.3 indicates normal lactose digestion and a ratio approaching 1.0 is observed in hypolactasia [34]. The measurement of stool pH and reducing substances in the stools has been used to assess lactose digestion in children. The analyses are easy to perform and convenient for the patient. However, stool pH has been shown to be unreliable in the diagnosis of hypolactasia in children and adults [34]. Furthermore, changes in gut motility and water excretion can alter the level of reducing substances in the stool. Thus, diagnosis of hypolactasia should not be based on stool tests alone [34]. Breath tests are most widely used to diagnose maldigestion. The principle behind breath tests is that lactose, which escapes digestion in the small intestine, is fermented by bacteria in the colon, producing short-chain fatty acids and hydrogen, carbon dioxide, and methane (in some individuals) gases. One breath test measures the amount of 13CO2 excreted in the breath following administration of 13C-lactose [34]. This stable isotope test has the advantage over older tests employing radioactive 14C-lactose, but the high cost of the equipment prohibits widespread use of this method. The current ‘‘gold standard’’ for diagnosis of carbohydrate maldigestion is the breath hydrogen test. 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, with ultimate pulmonary excretion [35]. The hydrogen breath test is widely used because it is noninvasive and easy to perform. Typically, a subject is given an oral dose of lactose following an overnight (ⱖ12 hours) fast. Breath samples are collected at regular intervals for a period of 3–8 hours. In early studies, 50 g of lactose was used as a challenge dose. Almost all lactose maldigesters will experience intolerance symptoms following a dose of lactose this large [30], and yet many will be able to tolerate smaller, more physiologic doses of lactose. Doses of lactose that are in the range of 1–2 cups (240–480 ml) of milk (12–24 g lactose) have recently been more frequently used [36]. The dose of lactose used in the breath hydrogen test influences the diagnostic criterion for lactose maldigestion. Early studies with 50 g lactose showed perfect separation of lactose digesters from maldigesters using a rise in breath hydrogen of greater than 20 parts per million (ppm) above the fasting level [37]. More recently, Strocchi et al. [38] evaluated different criteria for diagnosis of carbohydrate maldigestion, using small doses of carbohydrate (10 g lactulose). Using a cutpoint of ⱖ10 ppm rise in breath hydrogen above fasting over an 8-hour period resulted in improved sensitivity (93% vs. 76%) and only a slight decrease in specificity (95% vs. 100%) compared to the 20-ppm cutoff. Further, it was shown that using a sum of hydrogens from hours 5, 6, and 7 and a ⱖ15-ppm above fasting cutpoint resulted in 100% sensitivity and specificity. Despite the advantages of breath hydrogen testing, care must be taken to ensure an accurate test. First, it is important

to establish a low baseline breath hydrogen value, to which subsequent values are compared. This is accomplished by fasting before and after consumption of the lactose dose. In addition, it has been shown that a meal low in nondigestible carbohydrate (e.g., white rice and ground meat) the evening before the test results in lower baseline hydrogen [39]. Second, it is possible that some individuals may have a colonic microflora that is incapable of producing hydrogen. However, these individuals are rare and the possibility of a non-hydrogen-producing flora can be ruled out by the administration of lactulose [38]. Third, approximately 40% of adults harbor significant numbers of methane-producing bacteria in the colon [40]. Because methanogenic bacteria consume four parts of hydrogen to produce one part methane [40], some authors have suggested that simultaneous measurement of methane will improve the accuracy of breath hydrogen testing in methane-producing subjects [41]. The availability of gas chromatographs that can analyze both hydrogen and methane in breath samples eliminates this potential problem. Finally, a number of factors (sleep, antibiotics, smoking, bacterial overgrowth of the small intestine, and exercise) may complicate the interpretation of breath hydrogen tests [34]. Therefore, standardization of the breath test protocol and appropriate controls are important.

VI. LACTOSE MALDIGESTION AND INTOLERANCE SYMPTOMS A positive breath hydrogen test is indicative of lactose maldigestion. However, reduced lactase levels do not necessarily lead to intolerance symptoms. Symptoms of intolerance occur when the amount of lactose consumed exceeds the ability of both the small intestine and colon to effectively metabolize the dose. Unhydrolyzed lactose passes from the small intestine to the large intestine where it is fermented by enteric bacteria, producing the gases that are partially responsible for causing intolerance symptoms. The intensity of symptoms varies with the amount of lactose consumed [31, 42–44], the degree of colonic adaptation [45, 46] and the physical form of the lactose-containing food [47]. The correlation between lactose maldigestion and reported intolerance symptoms is unclear. Most maldigesters can tolerate the amount of lactose in up to 1–2 cups of milk without experiencing severe symptoms. However, some lactose maldigesters believe that small amounts of lactose, such as the amount used with coffee or cereal, cause gastrointestinal distress [48]. Individual differences observed in symptom reporting may reflect learned behaviors, cultural attitudes, or other social issues. Lactose maldigesters, unselected for their degree of lactose intolerance, tolerated a cup of milk without experiencing appreciable symptoms [49–51]. However, the results of these studies did not gain general acceptance, in part because of failure to utilize subjects with ‘‘severe’’ lactose intolerance. In 1995, Suarez et al. [48] conducted a study in 30

CHAPTER 37 self-described ‘‘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. 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.

VII. LACTOSE DIGESTION, CALCIUM, AND OSTEOPOROSIS Individuals who are lactose intolerant can tolerate moderate amounts of lactose with minimal to no gastrointestinal discomfort [48, 52], however, some lactose maldigesting individuals may unnecessarily restrict their intake of lactosecontaining, calcium-rich dairy foods, thus compromising calcium intake. Milk and milk products contribute 73% of the calcium to the U.S. food supply [53]. Lactose maldigestion is associated with lower calcium intakes and is more frequent in osteoporotic patients than in controls [54–57]. For example, Newcomer et al. [54] found that 8 of 30 women with osteoporosis were lactose maldigesters compared to only 1 of 30 controls. In addition, calcium intakes of LNP postmenopausal women in this study (530 mg/day) were significantly lower than in the lactase persistent women (811 mg/day). Interestingly, in this report, and another by Horowitz et al. [55], few of the LNP subjects reported a history of milk intolerance and yet they still restricted milk intake. The lower milk intakes in these subjects may have been due to factors other than lactose intolerance. However, it is also possible that these subjects restricted their milk intakes due to lactose intolerance in childhood, forgot that they had done so, and simply maintained that pattern of milk intake throughout life. Another potential explanation for the increased prevalence of osteoporosis among lactose maldigesters is that maldigestion of lactose decreases absorption of calcium. Human and animal studies suggest that lactose stimulates the intestinal absorption of calcium [53]. However, there is considerable disagreement regarding the influence of lactose and lactose maldigestion on calcium absorption in adults. This disagreement results from a number of factors including the dose of lactose given, the choice of method for assessing calcium absorption (single isotope, double isotope, balance methods), prior calcium intake of the subjects, and the form in which the calcium is given (milk vs. water). Kocian et al. [58], using a single-isotope (47Ca) method, demonstrated improved absorption of a 972-mg calcium dose from lactose-hydrolyzed milk as compared to milk containing lactose in lactose maldigesters. Conversely, the regular milk resulted in increased calcium absorption versus the lactose-hydrolyzed milk in lactose digesters. Another study, using dual-isotope methods, a 50-g lactose load, and 500 mg

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of calcium chloride in water found similar results [59]. Total fractional calcium absorption was decreased in maldigesters and increased in digesters with lactose feeding. However, the doses of lactose given in these studies (39–50 g or the equivalent of 3–4 cups of milk) were unphysiologic and may have resulted in more rapid intestinal transit than would be observed with more physiologic amounts of lactose. Several studies have been conducted with physiologic doses of lactose. Griessen et al. [60], using dual-isotope methods, found that lactose maldigesters (n ⫽ 7) had a slightly, but not statistically significantly, greater total fractional calcium absorption from 500 mL of milk compared to 500 mL of lactose-free milk. They also observed a nonsignificant decline in fractional calcium absorption in normal subjects (n ⫽ 8) when comparing lactose-free milk with regular milk. In another dual-isotope study, lactose maldigesters absorbed more calcium from a 240-mL dose of milk than did digesters (about 35% vs. 25%), which was thought to be due to lower calcium intakes in the lactose maldigesting group [61]. Most importantly, however, no difference was observed in fractional calcium absorption between lactosehydrolyzed and regular milk in either group of subjects. Finally, calcium absorption from milk and yogurt, each containing 270 mg of calcium, was studied in our laboratory using a single-isotope method [62]. No significant differences were observed in calcium absorption between milk and yogurt in either the lactose maldigesting or digesting subjects. Interestingly, yogurt resulted in slightly, but significantly (p ⬍ 0.05), greater calcium absorption in lactose maldigesters when compared to lactose digesters. Differences in study methodology (milk vs. water, dose of lactose, and the choice of method for determining calcium absorption) may explain contrasting results. Physiologic doses of lactose (e.g., amounts provided by up to 2 cups of milk) are not likely to have a significant impact on calcium absorption. The increased prevalence of osteoporosis in lactose maldigesters is most likely related to inadequate calcium intake rather than impaired intestinal calcium absorption.

VIII. DIETARY MANAGEMENT FOR LACTOSE MALDIGESTION It is difficult for lactose maldigesters to consume adequate amounts of calcium if dairy products are eliminated from the diet. Fortunately, lactose intolerance is easily managed. Dietary management approaches that effectively reduce or eliminate intolerance symptoms are discussed below and shown in Table 4.

A. Dose Response to Lactose There is a clear-cut relationship between the dose of lactose consumed and the symptomatic response. Small doses (up to

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Factors affecting lactose digestion

Dietary Strategies for Lactose Intolerance Dietary strategy

References

Dose of lactose

Consume a cup 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. Consume yogurts containing active bacteria cultures. A serving, or even two, 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 supplements (pills, capsules, and drops) may be used when large doses of lactose (⬎12 g) are consumed at once. Lactose-hydrolyzed milks also are well tolerated

Yogurts

Digestive aids

Colon adaptation

Consume lactose-containing foods daily to increase the colon bacteria’s ability to metabolize undigested lactose.

12 g of lactose) yield no symptoms [1, 48, 50–52], whereas high doses (⬎20–50 g of lactose) produce appreciable symptoms in most individuals [1, 63–65]. In a well-controlled trial, Newcomer et al. [1] demonstrated that ⬎85% of lactose maldigesters developed intolerance symptoms after consuming 50 g of lactose (the approximate amount of lactose in 1 quart of milk) as a single dose. The frequency of reported symptoms may be attributed to the nonphysiologic nature of the lactose dose and the physical form of lactose load administered. A physiologic dose containing 15–25 g of lactose is adequate to produce appreciable symptoms in some subjects [30, 66]. The incidence of symptom reporting generally remains above 50% with intermediate doses. However, the frequency varies from less than 40% to greater than 90% [30]. In a double-blind protocol, Suarez et al. [48] demonstrated that feeding 12 g of lactose with a meal resulted in minimal to no symptoms in maldigesters. Interestingly, in unblinded studies [66, 67], lactose maldigesters more frequently reported intolerance symptoms after consuming lactose loads similar to that given by Suarez et al. Recently, Suarez et al. [52] provided further evidence that individuals who are lactose intolerant can consume lactose-containing foods without experiencing appreciable symptoms by feeding lactose maldigesters 2 cups of milk daily. One cup of milk was given with breakfast, and the second was given

Suarez et al. (1995)48 Hertzler et al. (1996)6 Suarez et al. (1997)52 Solomons et al. (1985)69 Martini and Savaiano (1988)4 Dehkordi et al. (1995)70 Kolars et al. (1984)77 Gilliland and Kim (1984)83 Savaiano et al. (1984)47 Shermak et al. (1995)82 Savaiano et al. (1984)47 Kolars et al. (1984)83 Gilliland and Kim (1984)77 Moskovitz et al. (1987)97 Lin et al. (1993)94 Ramirez et al. (1994)98 Nielsen et al. (1984)104 Biller et al. (1987)109 Rosado et al. (1989)106 Brand and Holt (1991)102 Perman et al. (1981)116 Florent et al. (1985)46 Hertzler et al. (1996)6

with the evening meal. The symptoms reported by maldigesters after consumption of 2 cups of milk were trivial. Symptoms from excessive lactose in the intestine may increase out of proportion to dosage, which raises the possibility that the absorption efficiency decreases with increased loads. Fractional lactose absorption is most likely influenced by dosage, with more effective absorption of small loads and less effective utilization of larger doses. Hertzler et al. [43], using breath hydrogen as an indicator, suggested that 2 g of lactose is almost completely absorbed, whereas there was some degree of maldigestion when a 6-g load was ingested. The only study directly measuring the lactose absorption efficiency in lactose maldigesting subjects is that of Bond and Levitt [68], who intubated the terminal ileum and then fed the subjects 14C lactose mixed with polyethylene glycol, a nonabsorbable volumetric marker. Analysis of the ratio of 14 C lactose to polyethylene glycol passing through the terminal ileum allowed researchers to calculate the percentage of lactose absorbed. On average, maldigesters absorbed about 40% of a 12.5-g lactose load, whereas the other 60% passed to the terminal ileum. However, sizable differences were seen in absorption efficiency among lactose maldigesters. These differences could represent differences in residual lactase efficiency and/or gastric emptying and intestinal transit time.

CHAPTER 37 B. Factors Affecting Gastrointestinal Transit of Lactose Consuming milk with other foods, rather than alone, can minimize symptoms from lactose maldigestion [4, 69, 70]. A probable explanation for these findings is that the presence of additional foods slows the intestinal transit of lactose. Slowed transit allows more contact between ingested lactose and residual lactase in the small intestine, thus improving lactose digestion. It is also possible that additional foods may simply slow the rate at which lactose arrives in the colon, because a delay in peak breath hydrogen production, rather than a significant decrease in total hydrogen production has been reported [4]. The slower fermentation of lactose might allow for more efficient disposal of fermentation gases, reducing the potential for symptoms. The energy content, fat content, and added components such as chocolate may influence gastrointestinal transit of lactose and subsequent lactose digestion. Leichter [71] showed that 50 g of lactose from whole milk (1050 mL) resulted in fewer symptoms (abdominal discomfort, bloating, and flatulence) compared to 50 g of lactose from either skim milk (1050 mL) or an aqueous solution (330 mL). However, only blood glucose was measured to determine lactose digestion and no statistical evaluation of symptoms was done in this study. Recent studies have demonstrated that higher fat milk may slightly decrease breath hydrogen relative to skim milk [70], but not improve intolerance [70, 72, 73]. Further, increasing the energy content or viscosity of milk has not been effective in improving lactose digestion or tolerance [74, 75]. Chocolate milk has been recommended for individuals who are lactose intolerant. Apparently, chocolate milk empties from the stomach more slowly than unflavored milk, possibly due to its higher osmolality or energy content [3]. Two reports have demonstrated improved lactose digestion (i.e., reduced breath hydrogen) from chocolate milk [70, 76], with fewer symptoms reported in one of these studies [76]. Clearly, consumption of milk with other foods results in improved tolerance compared to milk alone. Therefore, consuming small amounts of milk routinely with meals is a recommended approach for individuals who are lactose intolerant to obtain sufficient calcium from dairy products. These individuals might also try chocolate milk to improve tolerance.

C. Yogurts The lactose in yogurt with live cultures is digested better than lactose in milk and is well tolerated by those who are lactose intolerant [77]. Prior to fermentation, most commercially produced yogurt is nearly 6% lactose due to the addition of milk solids to milk during yogurt production. However, as the lactic acid bacteria (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarius

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subsp. thermophilus) multiply to nearly 100 million organisms per milliliter, 20–30% of the lactose is utilized, decreasing the lactose content of yogurt to approximately 4% [78]. During fermentation, the activity of the ␤-galactosidase enzyme substantially increases. Casein, calcium phosphate, and lactate in yogurt act as buffers in the acidic environment of the stomach, thus protecting a portion of the microbial lactase from degradation and allowing the delivery of intact cells to the small intestine [79, 80]. In the duodenum, once the intact bacterial cells interact with bile acids, they are disrupted allowing substrate access to enzyme activity. Yogurt consumption results in enhanced digestion of lactose and improved tolerance [47, 77, 81–83]. In 1984, Kolars et al. [77] and Gilliland and Kim [83] reported enhanced lactose digestion from yogurt in lactose maldigesters. In both studies, breath hydrogen excretion was significantly reduced with the consumption of live culture yogurt. Furthermore, Kolars et al. [77] found that an 18-g load of lactose in yogurt resulted in significantly fewer intolerance symptoms reported by subjects as compared to the other forms of lactose given. Also in 1984, Savaiano et al. [47] demonstrated that yogurt feeding resulted in one-third to one-fifth less hydrogen excretion as compared to other lactose-containing dairy foods with no symptoms. Shermak et al. [82] reported that a 12-g load of lactose in yogurt resulted in lower peak hydrogen in children with a delay in the time for breath hydrogen to rise when compared to a similar lactose load given in milk. Moreover, the children experienced significantly fewer intolerance symptoms with yogurt consumption. Yogurt pasteurization following fermentation has been somewhat controversial [83]. One advantage of pasteurizing yogurt is a longer shelf life. However, removing the active cultures that are partly responsible for improved lactose digestion may increase lactose maldigestion and intolerance symptoms and cause lactose maldigesters to avoid yogurt products. Pasteurizing yogurt increases the maldigestion of lactose [47, 82, 83]. However, pasteurized yogurt is moderately well tolerated, producing minimal symptoms [47, 81, 82]. Because pasteurized yogurt is relatively well tolerated, other factors such as the physical form, or gelling, and the energy density of yogurt may play a role in tolerance. The level of the ␤-galactosidase enzyme in yogurt may not be the limiting factor for improving lactose digestion because not all yogurts have the same level of lactase activity [84]. Martini et al. [84] fed yogurts with varying levels of microbial ␤-galactosidase. The remaining characteristics of the test yogurts (pH, cell counts, and lactose concentrations) were similar. Despite the different levels of ␤-galactosidase activity, all yogurts equally improved lactose digestion and minimized intolerance symptoms.

D. Unfermented Acidophilus Milk Individuals who are lactose maldigesters [85–87] may consume unfermented milk containing cultures of Lactobacillus

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acidophilus in an effort to consume adequate amounts of calcium and avoid intolerance symptoms. Various strains of L. acidophilus exist, however strain NCFM has been most extensively studied and used in commercial products. Unfermented acidophilus milk tastes identical to unaltered milk because the NCFM strain does not multiply in the product, provided that the storage temperature is below 40F (5C) [85, 86, 88]. Lactobacillus acidophilus strain NCFM is derived from human fecal samples [79] and contains ␤-galactosidase (lactase). The effectiveness of acidophilus milk on improving lactose digestion and intolerance symptoms has been evaluated. Most evidence suggests that unfermented acidophilus milk does not enhance lactose digestion or reduce intolerance symptoms [47, 88–90] primarily due to the low concentration of the species in the milk. Improved lactose digestion has been observed by some [91]; however, the test milk in this study contained a much higher concentration of L. acidophilus than is normally used to produce commercial acidophilus milks. Further, the microbial lactase from L. acidophilus may not be available to hydrolyze the lactose in vivo [84, 86, 90]. Lactobacillus acidophilus is not a bile-sensitive organism [79, 88]. Therefore, once the intact bacterial cells reach the small intestine, bile acids may not disrupt the cell membrane to allow the release of the microbial lactase. However, sonicated acidophilus milk improved lactose digestion by reducing breath hydrogen [92]. Thus, if less bile-resistant strains were developed and used in adequate amounts, these strains may allow the ␤-galactosidase to be released, possibly yielding an effective approach to the dietary management of lactose maldigestion.

E. Lactase Supplements and Lactose-Reduced Milks The use of lactase supplements and lactose-reduced dairy products is steadily growing in the United States. The leading brand in this industry, ‘‘Lactaid,’’ reported $126 million in sales for fiscal 1997. The number of new dairy product introductions categorized as low- or no-lactose rose 50% from 1992 to 1997 [93]. Lactase pills, capsules, and drops contain lactase derived from yeast (Kluyveromyces lactis) or fungal (Aspergillus niger, A. oryzae) sources. Dosages of lactase per pill or caplet vary from 3000 to 9000 FCC units [94, 95]. Since 1984, these over-the-counter preparations have been generally recognized as safe by the U.S. Food and Drug Administration [96]. Additionally, milk that has been treated with lactase, resulting in a 70–100% reduction in lactose, is commercially available [95]. A number of studies have evaluated the effectiveness of these products. Doses of 3000–6000 Food Chemicals Codex (FCC) 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 [94, 97, 98].

The decrease in breath hydrogen and symptoms is generally dose dependent. Doses up to 9900 FCC units may be needed for digestion of a large lactose load, such as 50 g of lactose [94, 99, 100]. Lactose-hydrolyzed milks also improve lactose tolerance in both children and adults [64, 65, 101–111]. A by-product of lactose-hydrolyzed milk is increased sweetness, due to the presence of free glucose [48]. This increased sweetness may increase its acceptability in children [104].

F. Colonic Fermentation and Colonic Bacterial Adaptation of Lactose The colonic bacteria ferment undigested lactose and produce short-chain fatty acids (SCFA) 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 loss of intestinal lactase activity in lactose maldigesters is permanent. Studies from Israel, India, and Thailand have reported that feeding 50 g of lactose or more per day for periods of 1–14 months has no impact on jejunal lactase activity [17, 112, 113]. Despite this fact, milk has been used successfully in the treatment of malnourished children in areas of the world where lactose maldigestion is common. In Ethiopia, for example, 100 schoolchildren, aged 6–10 years, were fed 250 mL of milk per day for a period of 4 weeks [114]. While the children initially experienced some degree of gastrointestinal symptoms, the symptoms rapidly abated and returned to pretrial levels within 4 weeks. Similar results were observed with schoolchildren in India [112]. Finally, a study of African-Americans, who were lactose maldigesting and lactose intolerant aged 13–39 years, showed that 77% of the subjects could ultimately tolerate ⱖ12 g of lactose if lactose was increased gradually and fed daily over a period of 6–12 weeks [115]. Approximately 80% of the subjects (18 of 22) had rises in breath hydrogen of at least 10 ppm above baseline at the maximum dose of lactose tolerated, suggesting that improved digestion of lactose in the small intestine was not responsible for the increased tolerance. Therefore, the authors proposed that colonic bacterial adaptation was a likely explanation for these findings. Evidence for colonic bacterial adaptation to disaccharides (lactulose, lactose) is substantial. Perman et al. [116] fed adults 0.3 g/kg lactulose per day for 7 days and observed a decrease in fecal pH from 7.1  0.3 to 5.8  0.6. The breath hydrogen response to a challenge dose of lactose (0.3 g/kg) fell significantly after lactulose adaptation. Employing the same experimental design and doses of lactulose, Florent et al. [46] measured fecal ␤-galactosidase, colonic pH, breath hydrogen, fecal carbohydrates, SCFA, and 14C-lactulose catabolism in subjects before and after the 7-day lactulose maintenance period. Fecal ␤-galactosidase was six times

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FIGURE 1 Breath hydrogen response to a lactose challenge after lactose () or dextrose () feeding periods. Data are the means  SEM, n ⫽ 20. [Reprinted with permission from Hertzler, S. R., and Savaiano, D. A. (1996). Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. Am. J. Clin. Nutr. 64, 232–236.]

greater after lactulose feeding and breath hydrogen fell significantly. Breath 14CO2 (indicating catabolism of 14C-lactulose) increased and fecal outputs of lactulose and total hexose units were low after the lactulose feeding. Symptoms were not measured; however, a follow-up study showed that adaptation to lactulose (40 g/day for 8 days) reduced symptoms of diarrhea induced by a large dose (60 g) of lactulose [117]. Breath hydrogen decreased significantly and fecal ␤-galactosidase activity increased as in the previous study. Finally, two feeding trials adapting lactose maldigesters to lactose have been reported. The first was a blinded, crossover study from our laboratory at the University of Minnesota [45]. Feeding increasing doses of lactose (from 0.3 up to 1.0 g/kg/day) for 16 days resulted in a threefold increase in fecal ␤-galactosidase activity, which returned to baseline levels within 48 hours after substitution of dextrose for lactose. Further, 10 days of lactose feeding (from 0.6 up to 1.0 g/kg/day), compared to dextrose feeding, dramatically decreased the breath hydrogen response to a lactose challenge dose (0.35 g/kg) (see Fig. 1). In fact, after lactose adaptation, the subjects no longer appeared to be lactose maldigesters, based on a 20-ppm rise in breath hydrogen above fasting. The large doses of lactose fed during the adaptation period (averaging 42–70 g/day) resulted in only minor symptoms. Additionally, the severity and frequency of flatus symptoms in response to the lactose challenge dose were reduced by 50%. The second study was a double-blind, placebo-controlled trial conducted in France with a group of 46 subjects who were lactose intolerant [118]. Following a baseline lactose challenge with 50 g of lactose, subjects were randomly assigned to either a lactose-fed group (n ⫽ 24) or a sucrosefed control group (n ⫽ 22). Subjects were fed 34 g of either

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lactose or sucrose per day for 15 days. Fecal ␤-galactosidase increased and breath hydrogen decreased as the result of lactose feeding. Clinical symptoms (except diarrhea) were 50% less severe after lactose feeding. However, the sucrosefed control group also experienced a comparable decrease in symptoms, despite no evidence of metabolic adaptation. Thus, these authors concluded that the improvements in symptoms resulted from familiarization with the test protocol rather than from metabolic adaptation. Colonic bacteria develop an increased ability to ferment lactose (indicated by increased fecal ␤-galactosidase) following prolonged lactose feeding. Because hydrogen gas is an endproduct of fermentation, one might expect that the increased ability to ferment lactose would result in an increase, rather than the observed decrease, in breath hydrogen. However, breath hydrogen excretion represents the net of bacterial hydrogen production and consumption in the colon [40]. A decrease in net production of hydrogen could result from either decreased bacterial production or increased consumption. To examine the mechanism for decreased breath hydrogen after lactose adaptation, we employed metabolic inhibitors of bacterial hydrogen consumption (methanogenesis, sulfate reduction, and acetogenesis) to obtain measures of absolute hydrogen production [119]. Subjects were fed increasing amounts of lactose or dextrose in a manner similar to previous studies. Fecal samples were assayed in vitro for absolute hydrogen production and hydrogen consumption. Absolute hydrogen production after 3 hours of incubation with lactose was threefold lower after lactose adaptation (242  54 ␮L) compared to the dextrose feeding period (680  79 ␮L, p ⫽ 0.006). Fecal hydrogen consumption was unaffected by either feeding period. These findings tend to support the hypothesis that prolonged lactose feeding favors the growth or metabolic activity of bacteria (e.g., bifidobacteria, lactic acid bacteria) that can ferment lactose without the production of hydrogen. Feeding lactose, lactulose, and nonabsorbable oligosaccharides stimulates the proliferation of lactic acid bacteria in the colon [120–122]. Additionally, high populations of bifidobacteria inhibit the growth of known hydrogen-producing organisms, such as clostridia or Escherichia coli [123]. Colonic bacterial adaptation to lactose does occur. Although the role of colonic adaptation in improving symptoms is not firmly established, it is clear that many individuals who are lactose intolerant can 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.

IX. GENE THERAPY FOR LACTOSE INTOLERANCE Although conventional dietary therapies for lactose intolerance exist, the possibility of gene therapy for lactase nonpersistence was examined by During et al. [124]. An

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adeno-associated virus vector was orally administered to hypolactasic rats to increase lactase mRNA. The adenoassociated virus vector is a defective, helper-dependent virus and the wild type is nonpathogenic in humans and other species. Following a single administration of a recombinant adeno-associated virus vector expressing ␤-galactosidase, all rats treated with this vector (n ⫽ 4) were positive for lacZ mRNA in the proximal intestine within 3 days. There was no lactase mRNA in the rats treated with the control vector. On day 7, following vector administration, the rats were challenged with a lactose solution. The treated rats had a rise in blood glucose from 114  4 to 130  3 mg/dL after 30 minutes, while the control rats had a flat blood glucose curve. Further, the treated rats still displayed similar lactase activity when challenged with lactose 6 months later. Thus, the potential of gene therapy for lactose intolerance exists.

7. 8.

9.

10.

11.

X. SUMMARY A majority of the world’s population and approximately 25% of the U.S. population are lactose maldigesters. Milk and milk products not only contain lactose, but are also important sources of calcium, riboflavin, and high-quality protein. Some maldigesters may avoid dairy products due to the perception that intolerance symptoms will inevitably follow dairy food consumption. Avoiding dairy products may limit calcium intake and bone density, thus increasing the risk for osteoporosis. Avoidance of milk and milk products is unnecessary since moderate lactose consumption does not produce a symptomatic response in maldigesters. Additionally, various dietary strategies effectively manage lactose intolerance by reducing or eliminating gastrointestinal symptoms. Dairy food consumption is possible for individuals who are lactose intolerant if simple dietary management strategies are incorporated into daily living.

12.

13.

14.

15. 16. 17. 18.

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