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INTRODUCTION Intolerance to lactose-containing foods (primarily dairy products) is a common problem . In Europe and the United States, the prevalence is 7 to 20 percent in Caucasians (being lowest in those of northern European extraction), and is as high as 80 to 95 percent among Native Americans, 65 to 75 percent among Africans and African Americans, and 50 percent in Hispanics . The prevalence exceeds 90 percent in some populations in eastern Asia.
Clinical symptoms of lactose intolerance include diarrhea, abdominal pain, and flatulence after ingestion of milk or milk-containing products. These symptoms have been attributed to low intestinal lactase levels, which may be due to mucosal injury or, much more commonly, reduced genetic expression of the enzyme lactase-phlorizin hydrolase. However, as will be discussed below, intolerance to dairy products is not always a result of lactase deficiency.
LACTOSE INTAKE Lactose intake varies with age. Among infants, carbohydrates, primarily lactose, account for 35 to 55 percent of daily calories ingested. Lactose intake falls as weaning foods are introduced and eventually approaches the level ingested by adults. On a typical western diet, the average adult ingests approximately 300 g of carbohydrates per day. Of these carbohydrates, approximately 52 percent are starch (mainly cereals and potatoes), 37 percent sucrose, 5 percent lactose (mainly in milk), and 3 percent as fructose (in fruit and honey). Glycogen, glucose, maltose, and cellulose are minor constituents of the diet.
LACTOSE DIGESTION Lactose digestion is the rate-limiting step in the overall process of its absorption. Lactose is hydrolyzed by intestinal lactase to glucose and galactose on the microvillus membrane of the intestinal adsorptive cells . Uptake of these monosaccharides is accomplished by the sodium-dependent glucose carrier. Defects in this transporter result in severe diarrhea following carbohydrate intake .
Colonic salvage of nonabsorbed lactase Lactose that is not absorbed by the small bowel is passed rapidly into the colon. Up to 75 percent of lactose passes unabsorbed through the small intestine toward the cecum and colon in individuals with lactase deficiency . In the colon, lactose is converted to short-chain fatty acids and hydrogen gas by the bacterial flora, producing acetate, butyrate, and propionate. The short-chain fatty acids are absorbed by the colonic mucosa, thereby salvaging the malabsorbed lactose for energy utilization. This is a mechanism by which the newborn colon salvages lactose and by which the adult who has low intestinal lactase activity can adapt to persistent lactose ingestion. The production of hydrogen by colonic bacteria serves as the basis for the lactose breath hydrogen test used to diagnose lactose maldigestion (see "Lactose breath hydrogen test" below).
ETIOLOGY OF LACTOSE MALABSORPTION The causes of lactose malabsorption can be divided into primary lactase deficiency and lactase deficiency induced by underlying intestinal disease (show table 1).
There are three causes of primary lactose malabsorption:Racial or ethnic lactose malabsorption
Racial or ethnic lactose malabsorption Genetically determined reduction of lactase activity associated with racial or ethnic origin is the most common form of lactose malabsorption. The majority of the world's populations develop low intestinal lactase levels during mid-childhood (approximately at age five years). As noted above, this finding is most prominent in Asian and African populations; in contrast, the majority of Caucasians, particularly of Scandinavian background, have preservation of intestinal lactase activity into adulthood, inherited as an autosomal dominant trait . Although genetic analysis has established that lactase persistence in adulthood is inherited as an autosomal dominant trait , the molecular basis currently remains unknown.
Multiple single nucleotide polymorphisms in the DNA sequence of the coding region and the regulatory region of the lactase gene have been identified. Several haplotypes defined by such polymorphisms have been associated with persistence of elevated lactase expression. However, it is unclear whether these polymorphisms have a role in lactase gene expression . An analysis of Finnish families identified a single base polymorphism 13.9 kb upstream of the human lactase gene that correlates with biochemically assayed lactase non-persistence . The variant was identified in distantly related populations, suggesting that it is very old.
Functionally, the polymorphism affects transcriptional activity in in-vitro studies , and LPH mRNA levels in intestinal biopsy samples . The polymorphism modifies a transcription factor binding site, but the significance remains to be defined . If the correlation of the polymorphism with lactase non-persistence is confirmed by large scale studies, assessment of polymorphism may provide a more accurate and rapid means of diagnosis of lactose intolerance.
Expression patterns in transgenic mice indicate that most of the regulatory elements required for cell-specific regulation of rat, as well as rabbit, lactase are within the first two kb of 5' flanking sequence [12,13]. The transcription factors Cdx2, HNF-1a, and GATA are critical regulators of lactase expression [14,15]. All lactase genes examined so far, including the human gene, contain binding sites for these factors in the proximal promoter. In addition, the human genetic analysis indicates that the developmental decline may be regulated by more distant elements.
Molecular studies have generally found a positive correlation between lactase levels and lactase messenger ribonucleic acid (mRNA) expression, whether lactase activity is high or low [16-18]. This indicates that molecular regulation of this enzyme is at the level of gene transcription. In some subjects, however, there is a dissociation between lactase mRNA and lactase activity, suggesting that posttranscriptional factors also contribute to the decline in lactase biosynthesis, perhaps due to a partial block in transport of the enzyme from endoplasmic reticulum to the Golgi apparatus [18,19].
Immunohistochemical studies on small bowel biopsies have identified two patterns of immunoreactivity for lactase protein . Adults with lactase persistence displayed strong intestinal brush border staining, indicating the presence of lactase. Some of the subjects with hypolactasia showed no staining for lactase, while others showed a mosaic pattern in which small patches of enterocytes stained strongly, but there was no staining in the surrounding areas.
In the United States, lactase activity is normal in all healthy children of any racial or ethnic group until approximately five years of age. Thus, lactose intolerance detected in younger children usually indicates an underlying mucosal lesion or bacterial overgrowth syndrome.
The frequency of lactose maldigestion may increase with age and interact with racial predisposition . In one report, for example, lactose malabsorption was more prevalent in a group of individuals >74 years of age compared to the younger group (<65) . Although information of the individuals' ethnicity was not provided, the authors controlled for other potential confounders such as bacterial overgrowth and differences in intestinal transit.
Developmental lactase deficiency Developmental lactose malabsorption results from low lactase levels and is a consequence of prematurity. Lactase activity in the fetus increases late in gestation; thus, premature infants born at 28 to 32 weeks of gestation have reduced lactase activity . If these infants are otherwise healthy, their colons can salvage the unabsorbed carbohydrate, preventing malnutrition and diarrhea.
Congenital lactase deficiency Congenital lactase deficiency (CLD) is a rare autosomal recessive disorder. The largest number of reported cases worldwide has been described in the Finnish population. The disorder is characterized by the absence of lactase activity in the small intestine, with normal histologic findings and normal levels of other disaccharidases. Genetic analysis indicates that a gene located on the same chromosome, near, but distinct from, the lactase gene is responsible for CLD . Affected infants have diarrhea from birth, and have been reported to have hypercalcemia and nephrocalcinosis . This disorder was usually fatal prior to the development of lactose-free infant formulas.
Secondary lactose malabsorption Lactose malabsorption can be induced by a variety of acquired disorders:Bacterial overgrowth or stasis syndromes may be associated with increased fermentation of dietary lactose in the small bowel, often leading to symptoms of lactose intolerance. The diagnosis should be suspected from the clinical history and from a very early peak of breath hydrogen during lactose challenge.
Lactase is usually the first affected disaccharidase in these disorders, presumably because of its distal location on the villus. Treatment of the primary disorder can lead to restoration of lactase activity, which often lags behind the return of normal intestinal morphology. Lactose intolerance may persist for months after healing starts; this effect is unique to this enzyme and its biochemical basis is unexplained.
CLINICAL MANIFESTATIONS The term lactose intolerance is applied to the development of characteristic symptoms after the ingestion of lactose: abdominal pain, bloating, flatulence, diarrhea, and, particularly in adolescents, vomiting [27-29]. The abdominal pain may be crampy in nature and is often localized to the periumbilical area or lower quadrant. Borborygmi may be audible on physical examination and to the patient. The stools are usually bulky, frothy, and watery.
There is a variability of symptoms among patients with lactose intolerance. Important factors include the osmolality and fat content of the food in which the sugar is ingested, the rate of gastric emptying, the sensitivity to intestinal distension produced by the osmotic load of unhydrolyzed lactose in the upper small bowel, the rate of intestinal transit, and the response of the colon to the carbohydrate load. The following general principles apply to the patient with lactose intolerance :Meals with higher osmolality and fat content slow gastric emptying and reduce the severity of lactose-induced symptoms.
These subjective responses are difficult to quantify. As an example, patients with lactose intolerance who also have irritable bowel syndrome (IBS) may have increased pain after lactose ingestion. In one report of 427 healthy subjects, 24 percent had lactose intolerance and 15 percent had IBS . Although the frequency of lactose intolerance was not increased in the subjects with IBS, those with both disorders were much more likely to complain of symptoms of lactose intolerance than those with lactose intolerance alone (60 versus 27 percent). A five-year prospective study evaluated a lactose restricted diet in patients with lactose malabsorption and irritable bowel syndrome. The study demonstrated improvement in both short- and long-term symptoms as well as reducing outpatient visits by 75 percent  Other studies have confirmed the importance of subjective and perhaps psychologic factors in the development of lactose-induced symptoms . Given the similarity that may occur in symptoms, a lactose breath hydrogen test or an empiric trial of a lactose free diet should be part of the evaluation of patients suspected of having irritable bowel syndrome [31,33].Fecal flora can adapt to a chronic increase in dietary lactose, reducing the incidence and severity of symptoms following a lactose load. In a crossover study of this phenomenon, 20 patients with confirmed lactose maldigestion were randomized to lactose or dextrose supplementation for 10 days; the dose was gradually increased to 0.6 to 1.0 g/kg per day in three equal doses. There was no significant difference in symptoms during these periods . Lactose challenge was performed after an overnight fast at the end of these periods. Lactose supplementation was associated with a 50 percent reduction in flatus passage and severity and a marked reduction in the hourly breath hydrogen concentration.
However, somewhat different results were noted in another crossover trial with a similar design . Two weeks of lactose supplementation led to bacterial adaptation as evidenced by increased fecal beta-galactosidase activity and reduced breath hydrogen excretion after a lactose load. All symptoms except diarrhea regressed but equivalent clinical improvement occurred in the placebo group in which bacterial adaptation did not occur.
Relation of symptoms of lactose intolerance to lactose The preceding observation suggests that symptoms associated with lactose ingestion may not necessarily be related to lactose malabsorption. This hypothesis has been confirmed in a number of clinical reports. One study evaluated 30 subjects who complained of severe lactose intolerance who said they consistently developed symptoms after ingestion of less than 240 mL (8 oz) of milk . The ability to digest lactose was assessed by a breath hydrogen test after a lactose load, which was abnormal in 21 subjects. Daily during breakfast, the subjects were then given 240 mL of lactose-hydrolyzed milk containing 2 percent fat or 240 mL of 2 percent fat milk that was sweetened with aspartame to simulate the taste of lactose-hydrolysed milk. There was no difference in symptoms during the two study periods.
The authors drew two conclusions: symptoms in lactose maldigesting subjects with severe intolerance may mistakenly be attributed to lactose; and symptoms are likely to be negligible if lactose intake is limited to the equivalent of 240 mL of milk per day. A subsequent report from the same group found that 240 mL of milk could be tolerated twice daily if given in widely divided doses with food .
Similar observations were made in a study of 45 African-Americans with documented lactose maldigestion and intolerance to less than 240 mL of milk . Two-thirds reacted appropriately to the presence or absence of lactose in ingested milk but one-third had equivalent symptoms with lactose-containing and low-lactose milk.
Individuals with lactose malabsorption may still be able to tolerate a diet of calcium rich dairy products. A study involving women with lactose maldigestion demonstrated tolerance to a diet that provided 1500 mg of Ca/day by a variety of dairy products (hard cheese, yogurt, and milk) that were spread throughout the day . Another study involving adolescent girls with lactose maldigestion demonstrated that a dairy based diet providing 1200 mg of calcium per day was also well tolerated with negligible gastrointestinal symptoms .
DIAGNOSIS The term lactose malabsorption is generally reserved for those patients with typical symptoms in whom the intestinal malabsorption of lactose has been confirmed by a test of absorption (eg, lactose absorption test) or malabsorption (lactose breath hydrogen test). Less direct tests, such as low fecal pH or reducing substances in the stool, are only valid when lactose has been ingested, intestinal transit time is rapid, stools are collected fresh, assays are performed immediately, and bacterial metabolism of colonic carbohydrate is incomplete. The importance of confirming the diagnosis was illustrated in the preceding study of African Americans: 42 percent of 164 subjects who claimed to be intolerant of even small quantities of milk had normal breath hydrogen test results .
Lactose tolerance test The capacity for lactose absorption can be measured using a lactose absorption test. Following oral administration of a 50 g test dose in adults (or 2 g/kg in children), blood glucose levels are monitored at 0, 60, and 120 minutes. An increase in blood glucose by less than 20 mg/dL (1.1 mmol/L) plus the development of symptoms is diagnostic. False negative results may occur in patients with diabetes or bacterial overgrowth. Abnormal gastric emptying also can lead to spurious results; the blood glucose may be relatively higher with rapid emptying and depressed with delayed gastric emptying.
In adults, the lactose tolerance test has a sensitivity of 75 percent and a specificity of 96 percent . However, it is cumbersome (particularly in children), and time consuming, and has largely been replaced by the lactose breath hydrogen test.
Lactose breath hydrogen test The breath hydrogen test measures lactose nonabsorption. It is simple to perform, noninvasive, and has a sensitivity and specificity that are superior to the absorption test [39,40].
The test is begun by giving oral lactose in the fasting state, at a usual dose of 2 g/kg (maximum dose, 25 g). Breath hydrogen is sampled at baseline and at 30-minute intervals after the ingestion of lactose for three hours. The postlactose and baseline values are compared. We generally consider a breath hydrogen value of 10 ppm (parts per million) as normal. Values between 10 and 20 ppm may be indeterminate unless accompanied by symptoms, while values over 20 ppm are considered diagnostic of lactose malabsorption.
Both false-positive and false-negative results can occur. False-positive results are seen with inadequate pretest fasting or recent smoking; false-negative results can be seen after the recent use of antibiotics, in patients with lung disorders, or in the approximately 1 percent of subjects who are nonhydrogen producers. As noted above, intestinal lactase levels do not begin to fall until after age five. Thus, an abnormal lactose breath hydrogen test in children less than five years reflects either abnormal intestinal mucosa or bacterial overgrowth, both of which require further evaluation by appropriate diagnostic tests. A normal breath hydrogen test does not rule out an intestinal mucosal lesion and should not be used to avoid an intestinal biopsy.
On the other hand, small bowel biopsy cannot necessarily establish the diagnosis of disaccharidase deficiency. Although low values can identify subjects at risk for symptomatic lactose intolerance, low lactase activity induced by intestinal injury may be missed if the lesion is focal or patchy. Thus, clinical and biochemical data must always be compared to establish the diagnosis.
Once the diagnosis of lactose maldigestion is confirmed, the patient should be evaluated for one of the secondary causes described above (show table 1). Patients with a treatable underlying disorder may recover lactase activity and not require enzyme replacement. In infants and young children, the possibility of milk protein allergy should be excluded.
Normal breath hydrogen tests A significant proportion of patients with symptoms suggestive of lactose intolerance have normal breath hydrogen tests. In two series described above, for example, 30 and 42 percent of subjects with severe symptoms of milk intolerance had normal tests [29,36]. Other possibilities that must be considered include psychologic factors [31,32] and intolerance to other factors in milk.
Some patients have symptoms similar to those of lactose intolerance that are related to the maldigestion of other simple carbohydrates (eg, fructose, sorbitol) or of complex carbohydrates (eg, high-fiber foods). Thus, a careful dietary history should be obtained and appropriate breath hydrogen testing or dietary modification performed.
TREATMENT The treatment of lactose malabsorption in the absence of a correctable underlying disease includes four general principles:Reduced dietary lactose intake
Dietary lactose restriction When lactose restriction is necessary, the patient (or his or her parents) must be instructed to read labels of commercially prepared foods, as hidden lactose may be difficult to identify. By far the highest concentration of lactose per serving is present in milk and ice cream. Cheeses generally contain much lower quantities.
Complete restriction of lactose-containing foods should only be necessary for a limited period to ascertain the specificity of the diagnosis. Since some patients can tolerate graded increases in lactose intake, small quantities of lactose may subsequently be reintroduced into the diet, with careful attention being paid to development of associated symptoms. Because of its high sugar and fat content, ice cream may be a good way to introduce lactose into the diet. The diet should be reviewed with the patient to be certain that protein, fat, and other nutrients are supplied at appropriate levels.
Enzyme replacement Commercially available "lactase" preparations are actually bacterial or yeast beta-galactosidases. These supplements can, when added to lactose-containing food or ingested with meals containing lactose, reduce symptoms and breath hydrogen values in many lactose intolerant subjects. However, these products are not capable of completely hydrolyzing all dietary lactose, and the results achieved in individual patients are variable.
Among the commercial "lactase" preparations are Lactaid (tablets or liquid), Lactrase, LactAce, DairyEase, and Lactrol. Lactaid liquid can be added to milk (14 drops/quart) which is then refrigerated overnight before use. The resulting hydrolysis of lactose (which is virtually 100 percent effective) produces a sweeter taste than milk containing lactose . Commercially available predigested dairy products (eg, Lactaid milk) are also available.
Lactrase capsules can be sprinkled on or taken orally with lactose-containing foods, as can some of the other lactase preparations; however, the individual doses required and responses to individual products must be tested in each patient. "Acidophilus milk" is not sufficiently lactose-depleted to be useful.
It is possible that the efficacy of the different "lactase" preparations is not equivalent. A randomized, controlled trial compared the efficacy of three lactase preparations: Lactaid, Lactrase, and DairyEase . The results illustrated some of the difficulties in dissociation between objective measures (breath hydrogen) and subjective symptoms as noted above. Only Lactaid reduced breath hydrogen after a lactose load; however, Lactaid did not improve symptoms. On the other hand, Lactrase, which did not reduce breath hydrogen, diminished pain, bloating and total symptom scores, while Dairy Ease only improved pain. We generally recommend that individuals who have lactose intolerance start with two Lactaid tablets with lactose ingestion, and adjust both the Lactaid dose and the lactose load to tolerance.
Live culture yogurt, which contains endogenous beta-galactosidase, is an alternative source of calories and calcium, and may be well-tolerated by many lactose-intolerant patients. However, yogurts that contain milk or milk products added back after fermentation (such as many of the commercially available yogurt products in the United States) may produce symptoms.
Calcium intake Avoidance of milk and other dairy products can lead to reduced calcium intake, which may increase the risk for osteoporosis and fracture . One report demonstrated a strong correlation between bone mineral density values with the severity of symptoms and calcium intake in lactose intolerant young adults . Another study that focused on lactose intolerant Finnish women, mean calcium intake was significantly lower than in other women (570 versus 850 mg/day) and the adjusted odds ratio for nonankle lower body fractures was 2.15 . In a group of 30 pediatric patients (age 2 to 14) who had lactose restriction secondary to lactose intolerance, milk protein allergy, or hypercholesterolemia (mean Ca intake 270 mg/day) for two years, nine developed osteoporosis and six developed osteopenia .
We typically use calcium carbonate for calcium supplementation because it is the cheapest form available. Tums is popular and effective. Standard preparations contain 500 mg of calcium carbonate equivalent to 200 mg of elemental calcium, which is 20 percent of the United States Recommended Daily Allowance (USRDA) for adults. In infants and young children, liquid calcium gluconate is readily tolerated and available. When complete lactose restriction is recommended, the USRDA for calcium should be provided as a supplement.
Calcium supplementation in excess of 500 mg/day should be given in divided doses. Higher individual doses are associated with a plateau in calcium absorption that may prevent the attainment of positive calcium balance (show figure 1) .
The absorption of calcium carbonate, but not calcium citrate, is poor in patients with achlorhydria unless taken with meals . Although it might seem prudent to take calcium carbonate with meals, since it is often difficult to know who has achlorhydria, there is some evidence suggesting that taking calcium supplements with meals reduces iron absorption from food by about 50 percent. (See "Calcium supplementation in osteoporosis"). As a result, we usually recommend that patients take calcium carbonate with a low-iron meal (such as breakfast) to avoid possible iron deficiency. An alternative is calcium citrate (Citracal).
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