Lactose Malabsorption

Richard J. Grand, MD Robert K. Montgomery, PhD

Corresponding author Richard J. Grand, MD GI Cell and Molecular Biology Laboratory, Division of Gastroenterology and Nutrition, Department of Medicine, and General Clinical Research Center, Childrens Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA. E-mail: richard.grand@childrens.harvard.edu Current Treatment Options in Gastroenterology 2008, 11:1925 Current Medicine Group LLC ISSN 1092-8472 Copyright 2008 by Current Medicine Group LLC

Opinion statement
Lactose malabsorption is a syndrome producing a constellation of symptoms, including abdominal pain, bloating, atulence, diarrhea, and sometimes nausea and/or vomiting. Primary causes of lactose malabsorption due to loss of intestinal lactase activity include genetic/racial lactase nonpersistence, congenital lactase deciency, and developmental lactase deciency. Secondary lactose malabsorption can be caused by any disorder that injures the small intestinal mucosa, such as viral gastroenteritis, celiac disease, allergic (eosinophilic) gastroenteritis, and radiation enteritis. The diagnosis depends on careful clinical evaluation and is customarily conrmed with a lactose breath hydrogen test. As the symptoms are nonspecic, many adults diagnosed with lactose malabsorption actually have irritable bowel syndrome. Treatment consists of a trial of eliminating lactose-containing dairy foods, with supplementation of alternative calcium and protein sources. Commercial enzyme products containing -galactosidases can be prescribed to help patients digest dietary lactose. Long-term lactose restriction usually is not necessary and can lead to reduced bone mineral density.

Introduction
Lactose malabsorption, characterized by intolerance of dietary lactose, is a clinical syndrome producing a constellation of symptoms, including abdominal pain, bloating, flatulence, diarrhea, and sometimes nausea and/or vomiting [1]. Lactose (milk sugar) is a key nutrient in mammalian milk and the major carbohydrate source during the neonatal period. From an evolutionary and biological viewpoint, lactose is a unique sugar, as only in milk does it exist as a free molecule. It is synthesized by lactose synthetase exclusively in the mammary gland of virtually all placental mammals (except the sea lion) during late pregnancy and lactation. Lactose concentration in milk is inversely related to the content fat and protein; human milk contains the highest concentration (7%) of lactose in mammals. Lactose is hydrolyzed to glucose and galactose by intestinal lactase or, more precisely, lactase-phlorizin hydrolase (LPH), an intrinsic microvillus membrane glycoprotein. The enzymes location on the intestinal cryptvillus axis (with maximal expression at the upper villus) makes it particularly sensitive to villus injury. Neither prolonged lactose ingestion in humans nor excluding lactose from the diet influences the small intestines capacity to absorb lactose, strongly suggesting that the enzyme activity is not directly regulated by substrate availability [2]. LPHs specific activity in the human intestine fits a well-described developmental pattern, one that depends upon genetic factors. In most of those who develop lactase nonpersistence in mid-childhood, the pattern is characterized by a late gestational (2732 weeks) rise, followed by persistence of lactase-specific activity until approximately age 5 years, with a fall thereafter to low adult levels. This pattern is characteristic of Asians, Africans, African Americans, and people living in the Mediterranean basin. Among whites, especially those from or derived from northern Europe and certain localized clusters of other racial origins, lactase-specific activity rises in gestation and remains at or slightly

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Small Bowel Disease (eosinophilic) gastroenteritis, and radiation enteritis. When the intestinal villi are injured, lactase usually is the first affected enzyme, presumably because of its distal location on the villus. Treatment of the primary disorder leads to restoration of lactase activity. Interestingly, lactose malabsorption may persist for months after healing is initiated [14].

below this level throughout adult life (known as lactase persistence) [3]. Lactase persistence and nonpersistence are regulated predominantly at the gene transcription level [4,5,6]. Extensive data indicate that persistence of high levels of LPH enzyme activity is an autosomaldominant trait, whereas lactase nonpersistence exhibits autosomal-recessive inheritance [7]. In general, as one examines the prevalence of adult lactase nonpersistence in European populations, one finds a south-to-north gradient. Southern Italian adults have a prevalence of lactose malabsorption of approximately 71%, whereas the Dutch and Danes have little of this phenotype in their white populations [8]. In the clinical setting, the genetic background of the patient complaining of lactose malabsorption symptoms must be considered. Genetic analyses of the lactase gene have identified regions in which specific polymorphisms are associated with lactase nonpersistence and persistence [9,10,11]. At present, it is unclear whether these polymorphisms play an important role in lactase expression or simply provide markers for an as-yet-unidentified regulatory element. Genetic testing for such regions is available, but a functional test, such as the lactose breath hydrogen test, gives better information about the patients tolerance of this nutrient [3,6]. In many people who have low intestinal lactase enzyme levels, lactose not adsorbed in the small bowel passes into the colon, where it undergoes fermentation by colonic flora to short-chain fatty acids and hydrogen gas. The short-chain fatty acids can be absorbed by the colonic mucosa, thereby salvaging malabsorbed lactose. Many adults who have small intestinal lactose malabsorption avoid clinical symptoms upon lactose ingestion through active bacterial metabolism of ingested lactose. Hydrogen production by colonic flora is the basis for the lactose breath hydrogen test used to diagnose lactose malabsorption [12,13]. Three forms of primary lactose malabsorption exist: 1) racial or ethnic lactase nonpersistence (already described), 2) congenital lactase deficiency, and 3) developmental lactase deficiency. Congenital lactase deficiency is an autosomal-recessive disorder. A few cases have been described in Finland. The absence of lactase activity in the small intestine, normal morphologic features, and normal levels of other intestinal enzymes characterize this very rare condition. Developmental lactose malabsorption results from low lactase activities in premature infants born before 32 weeks gestation. Surprisingly, healthy premature infants tolerate lactose feedings quite well and avoid symptomatic lactose malabsorption because their colonic flora salvage lactose not absorbed in the small intestine [14]. Secondary lactose malabsorption is a consequence of a variety of acquired disorders characterized by intestinal injury. Common causes of secondary lactose malabsorption include viral gastroenteritis, celiac disease, allergic

CLINICAL PRESENTATION AND DIAGNOSIS

Typical complaints of lactose malabsorption include abdominal pain, cramps, distention, nausea, flatulence, and diarrhea. In children and adolescents, vomiting may predominate [2,15]. Although patients commonly identify these symptoms as a consequence of milk intolerance, they can be based on the inability to digest lactose or on sensitivity to milk proteins. Lactose malabsorption is often termed lactose intolerance. Strictly speaking, lactose malabsorption is a term reserved for those patients in whom the intestinal handling of lactose has been confirmed using appropriate tests of lactose absorption (lactose absorption tests) or malabsorption (lactose breath hydrogen tests) [12]. Lactose intolerance is characterized by symptoms, as described previously, after the ingestion of a test dose of lactose in food or milk. Lactase deficiency is defined only when low (> 2 SDs below the mean) or, very rarely, no level of lactase activity is found in a small intestinal biopsy sample appropriately assayed. Regardless of whether the cause of lactose malabsorption is primary or secondary, the clinical findings remain similar. The abdominal pain may be cramping in nature and often is localized to the periumbilical area or lower quadrants. Borborygmi may be audible on physical examination and to the patient. The stools may be bulky, frothy, or watery. Symptom variability among patients with lactose malabsorption is dependent on several factors: the osmolality and fat content of the food in which lactose is ingested, the gastric emptying rate, the quantity of fluid secreted by the intestine in response to the osmotic load of unhydrolyzed lactose in the upper small bowel, the individuals sensitivity to intestinal distention, the intestinal transit rate, and the colons response to the carbohydrate load. Foods with higher osmolality and fat content tend to slow gastric emptying and may reduce lactose-induced symptom intensity. People with more rapid intestinal transit generally are more symptomatic. Individuals with heightened sensitivity to intestinal distention have exaggerated symptoms similar to those of irritable bowel syndrome and visceral hyperalgesia [16,17]. Furthermore, patients with irritable bowel syndrome are often misdiagnosed as having lactose intolerance. The lactose malabsorption diagnosis is based on a combination of clinical findings and the results of appropriate tests. The use of screening tests for lactose malabsorption and the diagnosis of lactose intolerance

Lactose Malabsorption have evolved over time, and the lactose breath hydrogen test is now the preferred diagnostic modality. The presence of low fecal pH and reducing substances accompanying lactose ingestion indicates lactose malabsorption, but these tests are only valid when lactose has been ingested recently, intestinal transit time is rapid, stools are collected fresh and assayed immediately, and bacterial metabolism of colonic carbohydrate is incomplete. In general, lactose malabsorption is best confirmed using more specific tests. Lactose absorption capacity can be confirmed with the lactose absorption test. This test is similar to the oral glucose tolerance test. A fasting blood sample is obtained for glucose measurement, and the patient subsequently ingests 2 g/kg of body weight (maximum of 50 g) of lactose in a water solution. Blood is then drawn at 30, 60, 120, and 180 minutes. This test has a sensitivity of 75% and a specificity of 96% in adults. However, in children, it is cumbersome, invasive, and time-consuming; accordingly, the lactose breath hydrogen test [12,18] is the preferred diagnostic test in children. Although the lactose breath hydrogen test actually measures lactose nonabsorption rather than lactose hydrolysis and monosaccharide uptake, its sensitivity and specificity (both nearly 100%) are superior to those for the lactose absorption test, and it is simple and noninvasive. The breath test is performed in a fasting patient, and baseline breath hydrogen values are obtained. A dose of lactose (2 g/kg of body weight, maximum dose of 25 g) in water is administered comparable to that for the lactose absorption test, and breath hydrogen values are obtained at 30, 60, 90, 120, and 180 minutes. Peak hydrogen levels tend to occur between 90 and 120 minutes. A positive value is confirmed by a rise greater than 20 ppm over baseline after ingestion of the test substrate. Fasting values generally are less than 10 ppm, but levels below 20 ppm are acceptable. Elevated fasting breath hydrogen levels may be found if the test is performed shortly after smoking, after ingestion of toothpaste, or in the presence of bacterial overgrowth. Patients with cystic fibrosis also tend to have high fasting breath hydrogen levels. The test may be falsely negative in the small percentage (~ 1%) of the population that does not produce hydrogen [12,14]. The assay of lactose activity in small bowel biopsy samples establishes the presence of lactase deficiency. However, when lactase deficiency is due to intestinal injury, the lesion may be focal or patchy. Consequently, intestinal biopsy samples may show abnormal histology adjacent to a region with normal enzyme activity, or vice versa [19]. This test is invasive and time-consuming, as it is customarily performed during gastrointestinal endoscopy. Assays of tissue disaccharidases are available in only a few centers in the United States. Studies are available comparing intestinal histology, lactase activity, and breath hydrogen test results in

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children with chronic diarrhea or abdominal pain. In patients with abnormal histology, approximately 75% will have abnormal lactose breath hydrogen values (sensitivity 75%). However, in patients with normal histology, the lactose breath hydrogen test is only 54% specific, a reflection of the presence of a patchy villus lesion [19]. Very similar values are found when lactase activities on biopsy are compared with the results of breath hydrogen tests. Accordingly, an abnormal lactose breath hydrogen test is of value in identifying those patients who will be symptomatic after lactose ingestion. In children aged less than 5 years, an abnormal lactose breath hydrogen test normally signifies abnormal intestinal mucosa, which usually needs further definition with a small bowel biopsy. However, in such cases, a normal lactose breath hydrogen test does not rule out an intestinal mucosal abnormality and should not be used to avoid an intestinal biopsy in the diagnosis of suspected mucosal disease (eg, celiac disease) [14]. Subjective responses of individuals to ingested lactose vary widely, and anticipation of symptoms upon ingestion of milk can heighten some patients discomfort. One study evaluated 30 patients complaining of severe symptoms after low-level lactose ingestion (< 240 mL of milk) [15]. Lactose digestion was measured by a breath hydrogen test after a lactose load; the test was abnormal in 21 patients. During the test period, patients were then given 240 mL of lactose-hydrolyzed milk containing 2% fat or 240 mL of 2% fat milk sweetened with aspartame to mimic the taste of lactose-hydrolyzed milk. No difference in symptoms was seen during the two study periods. The authors drew two conclusions: 1) symptoms in those who maldigest lactose may be due to other disorders even when they are ascribed to lactase, and 2) symptoms appear to be minimal if lactose intake is restricted to the equivalent of 240 mL of milk per day. A subsequent report from the same investigators indicated that patients could tolerate 240 mL of milk if given twice daily in widely divided doses with food [20]. Similar findings were reported in a study of 45 black patients who had documented lactose maldigestion and intolerance to less than 240 mL of milk [21]. Two thirds responded as expected to the presence or absence of lactose in ingested milk, but one third had equivalent symptoms with lactose-containing and low-lactose milk. People who complain of lactose malabsorption often can tolerate a diet of calcium-rich dairy products. In one study, women with lactose maldigestion tolerated a diet providing 1500 mg of calcium per day via dairy products (hard cheese, yogurt, and milk) spread throughout the day [22]. In another study, adolescent girls with lactose maldigestion tolerated a dairy-based diet providing 1200 mg of calcium per day with negligible gastrointestinal symptoms [23].

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Small Bowel Disease

Treatment
The treatment of lactose malabsorption/intolerance includes four general principles: reduction or restriction of dietary lactose, substitution of alternate nutrient sources to avoid reductions in energy and protein intake, regulation of calcium and vitamin D intake, and use of a commercially available enzyme substitute.

Reduction or restriction of dietary lactose

Prolonged restriction of lactose-containing foods is not recommended. Complete lactose restriction generally is only necessary for a limited period to confirm the lactose malabsorption diagnosis. When lactose restriction is necessary, the patient (or, for children, the parents) must be instructed to read labels of commercially prepared foods, as hidden lactose may be difficult to identify. Milk and ice cream contain the highest concentrations of lactose per serving. Cheeses generally contain much lower quantities; camembert and roquefort contain virtually none. Some patients can tolerate graded increases in lactose intake after a short period of lactose restriction; thus, small quantities of lactose may be reintroduced into the diet while careful attention is paid to symptom development. Ice cream is often an excellent food for this purpose because of its high sugar and fat content. The diet should be re-evaluated regularly to ensure that the patient is receiving appropriate levels of protein, fat, and other nutrients.

Calcium and vitamin D

Avoiding milk and other dairy products over extended periods can lead to reduced calcium intake and increase the risk for osteoporosis and fracture [24,25]. Among 30 pediatric patients (aged 214 years) who had reduced their lactose ingestion for 2 years because of lactose intolerance, milk protein allergy, or hypercholesterolemia (mean calcium intake 270 mg/d) for 2 years, 15 developed low bone mineral density [26]. We customarily recommend calcium carbonate (Tums; GlaxoSmithKline, Inc., Research Triangle Park, NC) for calcium supplementation because it is the cheapest form available. Viactiv (McNeil Nutritionals, LLC, Fort Washington, PA) is also effective, although it contains 0.5 g of lactose per cube. This amount is unlikely to produce symptoms. In infants and young children, liquid calcium gluconate is readily tolerated and available. For all patients in whom lactose restriction is recommended, the US Reference Daily Intake for calcium should be provided as a supplement. When calcium supplementation in excess of 500 mg/d is indicated, the dose should be divided throughout the day. Approximately 1200 to 1500 mg/d are currently recommended for adolescents and young adults. Suggested intakes for adults depend upon the patients gender and menopausal status. At high individual doses, a plateau in calcium absorption may occur that may prevent the achievement of positive calcium balance [27]. Calcium carbonate, but not calcium citrate, is poorly absorbed in patients with achlorhydria unless taken with meals [28]. Although we advise patients to take calcium carbonate with meals to make it easy for them to remember, some evidence suggests that taking calcium supplements with meals reduces iron absorption from food by approximately

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50%. Accordingly, we suggest that patients take calcium carbonate with a low-iron meal (such as breakfast) to avoid possible iron deficiency. Although calcium citrate (Citracal; Bayer Corp., Pittsburgh, PA) is an alternative supplement, it also should be used with low-iron meals.

Vitamin D intake
Restriction of dairy products also may reduce the quantity of vitamin D consumed. Thus, the vitamin D status of patients who restrict their dairy product intake should be carefully monitored. A recent survey of healthy adolescents cared for in our hospital revealed that 24% had vitamin D deficiency [29]. Not surprisingly, factors associated with higher vitamin D levels were multivitamin intake and milk consumption. Lower vitamin D levels were associated with juice and soft drink consumption, higher body mass index, and African American ethnicity. Age-appropriate vitamin D supplementation accompanied by vitamin D status monitoring should be mandatory for patients who restrict milk intake, especially those at high risk for vitamin D deficiency (such as patients with malabsorption, Crohns disease, or celiac disease).

Enzyme substitutes
Commercially available lactase preparations are actually bacterial or yeast -galactosidases. These are added to lactose-containing food or ingested with meals containing lactose. These products lead to a reduction in symptoms and breath hydrogen values in many people with lactose malabsorption. However, these supplements do not completely hydrolyze all of the ingested dietary lactose, and the results in individual patients vary. A number of lactase preparations are sold in the large pharmacy chain stores and in health food stores across the United States. Among the most readily available of these are Lactaid (McNeil Nutritionals, LLC, Fort Washington, PA; tablets or liquid) and Lactrase (Schwarz Pharma, Monheim, Germany). Many of the products come in tablet or capsule form to be taken just before or with meals; others can be added to food upon ingestion or several hours earlier. When added to milk, the resulting hydrolysis of lactose (which can be highly efficient) may produce a sweeter taste than milk containing lactose [30]. Predigested dairy products (eg, Lactaid or DairyEase [Glenbrook Laboratories, New York, NY] milk) are also available. Some capsules can be opened and the contents sprinkled on lactose-containing foods. Doses required and responses to individual products must be tried by the patient. Acidophilus milk is not sufficiently lactose-depleted to be useful. The efficacy of these lactase preparations may not be equivalent. At least one randomized controlled trial compared the efficacy of three lactase preparations: Lactaid, Lactrase, and DairyEase [31]. There was some dissociation of objective measures (breath hydrogen) and subjective symptoms. Only Lactaid produced a fall in breath hydrogen after a lactose load, but Lactaid did not improve symptoms. Lactrase did not reduce breath hydrogen but diminished pain, bloating, and total symptom scores. In contrast, DairyEase only improved pain. The use of these enzyme products must be tailored to the patients age and requirements. Products that can be opened and sprinkled on food are most appropriate for children. For older patients, we generally recommend starting with two Lactaid tablets with lactose ingestion and adjusting the Lactaid dose and the lactose load to tolerance.

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Small Bowel Disease Live culture yogurt containing endogenous -galactosidase can be a valuable source of calories and will be well tolerated by many lactoseintolerant patients. It must be remembered that yogurts to which milk or milk products are added back after fermentation (such as many of the commercially available yogurt products in the United States) may produce symptoms.

Probiotics
Lactase-containing probiotics could potentially aid lactose digestion in people with lactose malabsorption. However, to date, studies that have evaluated such therapy have yielded discordant results; thus, their role in treating lactose-related symptoms remains unproven.

Disclosures
No potential conflict of interest relevant to this article was reported.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance
Chitkara DK, Montgomery RK, Grand RJ, Bller HA: Lactose intolerance. In Rose BD, ed. UpToDate [CD-ROM]. Waltham, MA: UpToDate; 2007. This is a frequently updated discussion of issues similar to those covered in this article. 2. Buller HA, Grand RJ: Lactose intolerance. Ann Rev Med 1990, 41:141148. 3. Grand RJ, Montgomery RK, Chitkara DK, Hirschhorn JN: Changing genes; losing lactase. Gut 2003, 52:617619. 4. Escher JC, de Koning ND, van Engen CG, et al.: Molecular basis of lactase levels in adult humans. J Clin Invest 1992, 89:480483. 5. Fajardo O, Naim HY, Lacey SW: The polymorphic expression of lactase in adults is regulated at the messenger RNA level. Gastroenterology 1994, 106:12331241. 6. Troelsen JT: Adult-type hypolactasia and regulation of lactase expression. Biochim Biophys Acta 2005, 1723:1932. An excellent review of the current cellular mechanisms regulating lactase expression in animals and humans. 7. Sahi T: Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol Suppl 1994, 202:720. 8. Scrimshaw NS, Murray EB: The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 1988, 48:10791159. 9. Enattah NS, Sahi T, Savilahti E, et al.: Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002, 30:233237. 10. Mulcare CA, Weale ME, Jones AL, et al.: The T allele of a single-nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C-13.9kbT) does not predict or cause the lactase-persistence phenotype in Africans. Am J Hum Genet 2004, 74:11021110. 11. Tishkoff SA, Reed FA, Ranciaro A, et al.: Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 2007, 39:3140. This study is similar to that in Mulcare et al. [10] but also demonstrates that lactase persistence appeared in different populations at similar times among milk drinkers. 1. Newcomer A, McGill D, Thomas P, Hofman A: Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med 1975, 293:12321236. 13. Shaw AD, Davies GJ: Lactose intolerance: problems in diagnosis and treatment. J Clin Gastroenterol 1999, 28:208216. 14. Heyman MB: Lactose intolerance in infants, children, and adolescents. Pediatrics 2006, 118:12791286. An important compendium of information regarding the function of lactose and lactase in newborns and young infants, with information regarding the treatment of lactase enzyme abnormalities in the young. This is a publication of the Committee on Nutrition of the American Academy of Pediatrics. 15. Suarez FL, Savaiano DA, Levitt MD: A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med 1995, 333:14. 16. Vesa T, Seppo L, Marteau P, et al.: Role of irritable bowel syndrome in subjective lactose intolerance. Am J Clin Nutr 1998, 67:710715. 17. Bohmer C, Tuynman H: The effect of a lactose-restricted diet in patients with a positive lactose tolerance test, earlier diagnosed as irritable bowel syndrome: a 5-year follow-up study. Eur J Gastroenterol Hepatol 2001, 13:941944. 18. Joseph F, Rosenberg AJ: Breath hydrogen testing: diseased versus normal patients. J Pediatr Gastroenterol Nutr 1988, 7:787788. 19. Hyams JS, Stafford RJ, Grand RJ, Watkins JB: Correlation of lactose breath hydrogen test, intestinal morphology, and lactase activity in young children. J Pediatr 1980, 97:609612. 20. Suarez FL, Savaiano D, Arbisi P, Levitt MD: Tolerance to the daily ingestion of two cups of milk by individuals claiming lactose intolerance. Am J Clin Nutr 1997, 65:15021506. 21. Johnson AO, Semenya JG, Buchowski MS, et al.: Correlation of lactose maldigestion, lactose intolerance, and milk intolerance. Am J Clin Nutr 1993, 57:399401. 12.

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22. 23. Suarez F, Adshead J, Furne J, Levitt M: Lactose maldigestion is not an impediment to the intake of 1500 mg calcium daily as dairy products. Am J Clin Nutr 1998, 68:11181122. Pribila BA, Hertzler SR, Martin BR, et al.: Improved lactose digestion and intolerance among African-American adolescent girls fed a dairy-rich diet. J Am Diet Assoc 2000, 100:524528. Di Stefano M, Veneto G, Malservisi S, et al.: Lactose malabsorption and intolerance and peak bone mass. Gastroenterology 2002, 122:17931799. Honkanen R, Kroger H, Alhava E, et al.: Lactose intolerance associated with fractures of weight-bearing bones in Finnish women aged 38-57 years. Bone 1997, 21:473477. Infante D, Tormo R: Risk of inadequate bone mineralization in diseases involving long-term suppression of dairy products. J Pediatr Gastroenterol Nutr 2000, 30:310313. Harvey JA, Zobitz MM, Pak CY: Dose dependency of calcium absorption: a comparison of calcium carbonate and calcium citrate. J Bone Miner Res 1988, 3:253258. 28. 29. 30.

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24. 25. 26. 27.

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Sheikh MS, Santa Ana CA, Nicar MJ, et al.: Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med 1987, 317:532536. Gordon CM, DePeter KC, Feldman HA, et al.: Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004, 158:531537. Rosado JL, Solomons NW, Lisker R, Bourges H: Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidase to milk at mealtime. Gastroenterology 1984, 87:10721082. Ramirez FC, Lee K, Graham DY: All lactase preparations are not the same: results of a prospective, randomized, placebo-controlled trial. Am J Gastroenterol 1994, 89:566570.