Milk and milk products contain high concentrations of the disaccharide lactose (galactose and glucose linked by a beta-galactoside bond). Intestinal absorption of lactose requires that the disaccharide be hydrolyzed to its component monosaccharides, both of which are rapidly transported across the small bowel mucosa. A brush border beta-galactosidase, lactase, carries out this hydrolysis. While infants virtually always have high concentrations of lactase, sometime after weaning a genetically programmed reduction in lactase synthesis results in very low lactase activity in some adult subjects, a situation known as lactase nonpersistence.
Lactase nonpersistence results in incomplete digestion of an ingested load of lactose, hence lactose is malabsorbed and reaches the colon. If sufficient lactose enters the colon, the subject may experience symptoms of abdominal pain, bloating, excess flatulence, and diarrhea, a condition known as lactose intolerance (LI). Diseases of the small bowel mucosa (infection, celiac disease) may also be associated with low brush border lactase, with resultant lactose malabsorption (LM) and LI.
The terminology involved in lactose absorption/intolerance is as follows:
- Lactase nonpersistence (or lactase insufficiency) – indicates that brush border lactase activity is only a small fraction of the infantile level, a condition documented by analysis of brush border biopsies. Recently it has been shown that a genotype (C/C) of the lactase promoter gene is responsible for lactase nonpersistence, and demonstration of this genotype can be used as indirect evidence of lactase nonpersistence.
- Lactose malabsorption – indicates that a sizable fraction of a dosage of lactose is not absorbed in the small bowel and thus is delivered to the colon. Since such malabsorption is virtually always a result of low levels of lactase, there is a nearly one to one relationship of lactase nonpersistence (or deficiency) and LM. LM is objectively demonstrated via measurements of breath H2 or blood glucose concentrations following ingestion of a lactose load.
- Lactose intolerance – indicates that malabsorbed lactose produces symptoms (diarrhea, abdominal discomfort, flatulence, or bloating). It should be stressed that this symptomatic response to LM is linked to the quantity of lactose malabsorbed (as well as other variables), i.e., ingestion of limited quantities of lactose does not cause recognizable symptoms in lactose malabsorbers, while very large doses commonly induce appreciable LI symptoms. As a result, the prevalence of lactase nonpersistence or LM could far exceed the prevalence of LI symptoms in population groups ingesting modest quantities of lactose.
A public health problem may arise when large numbers of individuals diagnose themselves as being lactose intolerant. However, these self-identified lactose intolerant individuals may actually be lactase persisters. Some of these lactase persisters (and even lactase nonpersisters) may mistakenly ascribe the symptoms of undiagnosed irritable bowel syndrome (IBS) or other intestinal disorders to LI. Given that the relatively nonspecific abdominal symptoms caused by IBS and lactose malabsorption are extremely susceptible to the placebo effect, reliable demonstration of LI requires double-blind methodology.
The problem may become intergenerational when self-diagnosed lactose intolerant parents place their children on lactose restricted diets (even in the absence of symptoms) or use enzymatic replacement in the belief that the condition is hereditary. Children and adults with lactose intolerance may avoid dietary milk intake to reduce symptoms of intolerance. Since the avoidance of milk and milk containing products can result in a dietary calcium intake that is below recommended levels of 1,000 milligrams (mg) per day for men and women and 1,300 mg for adolescents, osteoporosis and associated fractures secondary to inadequate dietary calcium is the perceived major potential health problem associated with real or assumed lactose intolerance.
Current dietary recommendations suggest consuming 3 cups/day of fat-free or low-fat milk or equivalent milk products. This amount is equivalent to about 50 grams of lactose, which we defined to be the threshold of minimum tolerance. We defined LI to be present when ingestion of 50 grams of lactose (or less) as a single dose by a lactose malabsorbing subject induces gastrointestinal (GI) symptoms not observed when the subject ingests an indistinguishable placebo.
Because ingesting smaller portions over the course of the day may minimize potential problems with larger acute lactose loads, the above definition of LI may miss lactose malabsorbers who ingest smaller dosages of lactose. The prevalence of clinically important LI requires demonstration that the quantity of lactose that subjects actually ingest (or wish to ingest) causes symptoms in placebo controlled experiments.
Treatment to reduce lactose exposure, while maintaining calcium intake from dairy products, consists of a lactose restricted diet or the use of milk in which the lactose has been pre-hydrolyzed via treatment with lactase supplements. Lactase supplements taken at the time of milk ingestion also are commercially available.
This report was commissioned as background material for a National Institutes of Health (NIH) and Office of Medical Applications of Research (OMAR) Consensus Development Conference on Lactose Intolerance and Health to address the following key questions:
Understanding the terminology of lactose-related “problems” is important and outlined as follows:
- Lactase deficiency – low concentrations of lactase in the small intestinal brush border relative to the concentrations observed in infants.
- Lactose malabsorption – failure of the small bowel to absorb the bulk of an ingested load of lactose.
- Lactose intolerance – a symptomatic response to malabsorption of lactose.
There are multiple causes of lactase deficiency. Congenital lactase deficiency, a very rare condition in which lactase synthesis is negligible at birth, results from the inheritance of two defective alleles of the lactase transcribing gene located on chromosome 2. Secondary lactase deficiency occurs in diseases that damage the brush border, such as celiac disease or intestinal infections. This deficiency usually is reversible with recovery from the disease. Lactase nonpersistence is a condition in which lactase synthesis is normal at birth and throughout infancy. However, after weaning, lactase synthesis declines, and by adulthood brush border lactase concentrations are only about 10 percent of the infantile level. This nonpersistence of lactase synthesis, which occurs despite continued exposure to milk or lactose, is present in about 70 percent of the world’s adult population. This review will focus solely on the problems associated with lactase nonpersistence.
Lactase nonpersistence versus persistence has been shown to be a function of a lactose promoter region located upstream from the lactase gene. In lactose nonpersistent subjects the activity of this promoter is programmed to decline markedly after weaning, with a resultant decline in lactase synthesis. Several population groups, most prominently individuals of northern European extraction, have mutations of this promoter which permits it to remain active throughout life. In northern Europeans, a single nucleotide thymine for cytosine substitution in the promoter region allows this gene to retain activity throughout adulthood with resultant lactase persistence. Lactose nonpersisters have a C/C genotype whereas persisters have a C/T or T/T genotype (the C → T mutation is a dominant trait).
Direct assessment of brush border lactase levels requires analysis of biopsies of small bowel mucosa via either measurement of enzymatic activity or histochemical staining for lactase. Genetic assessment of the C/T promoter area recently has become available. The complexity and expense of these techniques has limited their application, and information concerning the lactase nonpersistence/persistence state of individuals largely has been inferred from measurements of lactose absorption. The Digestive Diseases Clearinghouse of the National Institute of Diabetes, Digestive and Kidney Diseases states that 30 million to 50 million individuals in this country and about 4 billion people worldwide are lactase nonpersisters. Many of these individuals belong to minority groups such as Asians, African Americans, Hispanics, Native Americans, Alaskan Natives, and Pacific Islanders. However, lactase nonpersistence is also observed in a sizable fraction of Caucasians of southern European and Mediterranean origin.
Multiple tests have been employed to assess the ability of a subject to absorb lactose. Such testing initially employed measurements of the rise in blood glucose observed after ingestion of a large (50 gram) dose of lactose, the lactose content of one quart of cow’s milk. A rise of blood glucose of <20 mg was used as evidence of lactose malabsorption. This test largely has been supplanted by the hydrogen H2 breath test, which assesses breath H2 concentration following ingestion of a 50 gram dose of lactose. A rise in breath H2 signifies that lactose has reached the colonic bacteria and hence was malabsorbed. Various lactose dosages, times of breath collection, and breath H2 increases have been employed in this test, and the accuracy of hydrogen H2 breath testing for lactose malabsorption has never been precisely determined. Nevertheless, this simple noninvasive test has been widely employed and much of our knowledge concerning the prevalence of lactose malabsorption in various population groups, as well as the ability of individual patients to absorb lactose, has been obtained via hydrogen H2 breath testing.
Lactose intolerance indicates that malabsorption of lactose results in symptoms of diarrhea, flatulence, bloating, or abdominal discomfort. While LM and LI frequently are used interchangeably, the demonstration that an individual malabsorbs lactose does not necessarily indicate that the subject will be symptomatic. The likelihood that a lactose malabsorber will perceive symptoms after ingestion of lactose is a function of many variables, including the dosage of lactose, lactase activity of the mucosa, foods co-ingested with lactose, the lactose fermentation pathways of the colonic flora, and the sensitivity of an individual’s colon to lactose malabsorption. Of particular importance is the dosage of lactose. Intolerance to supra-physiological loads of lactose (such as were employed in the lactose tolerance test) does not necessarily indicate that subjects will be symptomatic with a smaller, more physiological dosage. Thus, the dosage of lactose that causes symptoms is a major consideration in determining the importance of lactose as a clinical problem. Another important question is the extent to which the colon of select individuals might be particularly sensitive to lactose and/or its bacterial metabolites; e.g., are patients with IBS unusually susceptible to lactose induced symptoms?
Treatment of Lactose Intolerance
LI may be self-diagnosed or diagnosed by a clinician based on historical information and/or the demonstration of lactose malabsorption. Blinded evaluation to document the role of lactose in a patient’s symptomatology is not employed. As a result, the subject’s unblinded response to a reduction in lactose intake is the standard means of establishing the diagnosis of lactose intolerance. Treatment to reduce lactose exposure consists of a lactose restricted diet or the use of lactase supplements. The former may involve the avoidance of milk and milk-containing foods or the use of milk in which the lactose has been pre-hydrolyzed via treatment with lactase. Lactase supplements taken at the time of milk ingestion also are commercially available.
Health Outcomes of Dairy Exclusion Diets
As described above, gastrointestinal symptoms are the main presenting clinical symptoms of LI and a major reason that individuals are presumed to be lactose intolerant. In attempts to reduce these symptoms, many exclude dairy from their diet. Others avoid dairy for cultural or health belief reasons (vegans), even if they do not have symptoms of LI. Osteoporosis and associated fractures secondary to inadequate dietary calcium is the perceived major long-term health outcome of interest associated with real or assumed LI, since the avoidance of milk and milk containing products usually results in a dietary calcium intake that is well below recommended levels of 1,000 mg per day for men and women and 1,300 mg for adolescents. Women who are pregnant or breastfeeding need between 1,000 and 1,300 mg of calcium daily. Because dairy foods are the major source of dietary calcium intake (in the absence of supplementation), dietary recommendations suggest consuming 3 cups/day of fat-free or low-fat milk or equivalent milk products. This amount could be ingested over the course of the day (e.g., 1 cup three times per day with each meal) to minimize potential problems with larger acute lactose loads. The recommended calcium intake by age group is shown in Table 1. Table 2 shows examples of calcium content in common foods.
Tolerable Dose of Lactose
Symptoms induced by lactose malabsorption (lactose intolerance) result from: (a) fluid osmotically “held” in the gut by nonabsorbed lactose and its bacterial metabolites and (b) gases released by the bacterial fermentation of lactose. Thus, unlike an allergic reaction that may be triggered by trivial doses of the allergen, a symptomatic response to LM requires that the mass of lactose reaching the colon be sufficient to hold enough water to induce diarrhea and/or permit gas production of a magnitude that causes abdominal pain, distention, or flatulence. It follows that very low doses of lactose should be tolerated without symptoms, while very large doses should routinely induce symptoms. Defining the dosage that is tolerable in lactose malabsorbers is crucial to determining the clinical importance of LM as well the prevalence of LI.
A variety of physiological differences between individuals indicates that there may be sizable individual differences in the dose of lactose that are tolerated by subjects with LM. Lactase nonpersistent subjects retain a low, but readily measureable, concentration of lactase in the brush border of their small bowel, and intubation studies have shown that these subjects are capable of absorbing variable amounts (mean: about 40 percent) of a 12 gram dose of lactose. The kinetics of this digestion have not been studied, but it seems likely that the 12 gram dose of lactose saturates the digestive activity of the gut, such that the percentage absorption would decline with increasing lactose loads. The tests employed to diagnose LM are qualitative and provide no information on the actual quantity of lactose not absorbed. It is possible that there are appreciable differences in the residual lactase activity of lactase nonpersistent subjects, with resultant sizable differences in their ability to digest and absorb a given dose of lactose. Differences in small bowel transit time (partially a function of gastric emptying) could affect the ability of this limited lactase activity to act on luminal lactose.
If the osmotic load created by nonabsorbed lactose was simply a function of the amount of lactose reaching the colon, the potential for nonabsorbed lactose to increase fecal water and induce diarrhea would be predictable: a gram of lactose is equivalent to 3 mosms and fecal water is isotonic (about 300 mosm/l). Thus, 12 grams of lactose (36 mosm), the quantity in 1 cup of milk, would osmotically hold 36/300 of a liter of fluid in the lumen or about 120 ml. Normally, humans excrete about 100 ml of fecal water each day, and increasing this quantity by 120 ml would yield a loose stool but not severe diarrhea. However, the vast majority of malabsorbed lactose is fermented by the colonic bacteria to short chain organic acids, which are rapidly taken up by the colonic mucosa. When relatively low amounts of lactose reach the colon, fermentation and subsequent absorption of lactose metabolites may be sufficiently rapid to remove all lactose and its metabolites from the fecal stream, thus protecting the subject from lactose-induced diarrhea. However, as the lactose load increases, the production of bacterial metabolites may outstrip the ability of the colonic mucosa to remove these metabolites. In this situation, bacterial metabolism increases the osmotic load over that of lactose with a resultant increase in fecal volume. Thus, differences in fecal bacterial metabolism, colonic mucosal function, and colonic transit time influence the susceptibility of individual subjects to develop diarrhea following malabsorption of lactose.
Colonic bacteria ferment lactose via gas producing and nongas producing pathways. Adaption of the colonic flora via a shift to nongas producing pathways is considered to be the explanation for the decreased H2 excretion that occurs following daily exposure to large doses of lactose. This fermentation pathway could reduce the distention and flatulence noted with lactose malabsorption. The quantitatively important gases directly released during fermentation of lactose are carbon dioxide (CO2) and hydrogen gas (H2). The third quantitatively important gas resulting from fermentation is methane (CH4), a product of methanogenic bacteria that utilize preformed H2 and CO2 to synthesize CH4, a reaction that results in a fivefold reduction in gas volume (1 CO2 + 4 H2 → 2 H2O + 1 CH4). In addition, several other bacterial reactions utilize H2, and H2 released from fecal material is only a small fraction of that produced. After leaving the feces, CO2 is very rapidly absorbed across the intestinal mucosa; H2 and CH4 are also absorbed, albeit at a slower rate than CO2. The luminal gases that escape metabolism and absorption are excreted per the anus and thus have the potential to increase flatus volume and frequency. Since there are individual differences in the gas producing and consuming reactions, it would be expected that the volume of luminal gas resulting from malabsorption of a given quantity of lactose might vary widely from one subject to the next.
Lastly, individuals differ in their response to colonic distention. Subjects with a “hypersensitive” colon may rapidly propel nonabsorbed lactose and its metabolites through the colon with resultant diarrhea and flatulence, while slower transit in the less sensitive colon could allow for more complete absorption of the metabolites, hence no diarrhea or flatulence. Similarly, the hypersensitive colon might perceive discomfort with a degree of distention that was imperceptible to subjects with a less sensitive colon.
The above theoretical discussion suggests that there could be wide individual differences in the daily dose of lactose that is tolerable to subjects with lactose nonpersistence. Elucidation of this tolerable dose can only be obtained from a study of the subjective response of subjects to ingestion of known dosages of lactose. Some of the many factors that could influence the results of such studies are:
- Psychological – The perception of symptoms such as bloating and discomfort resulting from dietary manipulations is very susceptible to psychological factors. Thus, reliable testing requires placebo controlled, double-blind methodology.
- Form that lactose is administered or restricted – The dietary load of lactose, rather than that of milk, should be manipulated to ensure that intolerance symptoms result from lactose rather than some nonlactose fraction of milk.
- Timing of lactose ingestion – Distributing lactose ingestion throughout the day very likely results in fewer symptoms than a similar quantity of lactose taken as a single dose.
- Food co-ingested with lactose – Food co-ingested with lactose would tend to reduce the rate of gastric emptying, which would slow the rate that lactose is presented to the small bowel and, hence, increase the fraction of lactose digested and slow the rate of presentation of unabsorbed lactose to the colon.
- Amount of lactose routinely ingested in diet – Some studies indicate that chronic ingestion of appreciable doses of lactose increases tolerance to lactose.
- “Sensitivity” of the colon – Subjects with a “hypersensitive” colon (i.e., IBS subjects) might be more susceptible to lactose-induced symptoms than are subjects who do not have IBS.
Strategies to Manage Individuals with Diagnosed Lactose Intolerance
Lactose is a simple disaccharide composed of glucose and galactose linked by a beta 1,4 bond. Intestinal brush border synthesizes lactase, an enzyme that is able to cleave the beta 1,4 bond. This hydrolysis is required for the intestinal absorption of lactose.
Probiotics are live microorganisms that are ingested to prevent or treat disease. The current definition by the Food and Drug Administration and the World Health Organization is “Live microorganisms which, when administered in adequate amounts, confer a health benefit on the host.” These microorganisms are a heterogeneous group that are nonpathogenic and have beta-galactosidase or lactase intracellularly and may aid in the digestion of lactose ingested by the host. These microorganisms can be added to food products, such as milk and yogurt, or used as supplements. Examples of commonly used probiotics include lactobacillus, bifidobacterium, and saccharomyces. Enzyme replacement therapy with lactase from nonhuman sources to hydrolyze lactose in another important approach to preventing lactose intolerance. There are multiple commercially available lactase supplements containing variable amounts of beta-galactosidase from a variety of sources. In addition, lactose reduced milk is also available commercially, with lactose content of 5 percent to 90 percent of regular milk.
Probiotics and lactase supplements are often regulated as dietary supplements rather than pharmaceuticals or biological agents. Hence, there is no requirement to demonstrate efficacy, purity, potency, or safety prior to marketing probiotics and supplements. The access to the World Wide Web and direct consumer marketing has inundated the public with promotional information, while scientific evidence to support use has been largely overlooked.
Another approach in management of lactose intolerance is to increase the lactose load steadily in one’s diet, giving the colon time to adapt. This is supported by the observation that introduction of lactose to diet causes temporary and transient symptoms in individuals.49 Since lactase from intestinal brush border is not an inducible enzyme, the reduction in symptoms may be explained by colonic adaptation. The time frame is approximately 1 week, as shown by Perman et al.151 that demonstrated increased beta-galactosidase activity and lactulose catabolism in the feces of healthy adults who consumed 40 gm lactulose per day for 1 week.
Other strategies for management of lactose intolerance include gut decontaminating agents and anti-microbials, such as rifaximin.
Key Questions Addressed in this Report
- What is the prevalence of lactose intolerance? How does this differ by race, ethnicity, and age?
- What are the health outcomes of dairy exclusion diets?
- In true lactase nonpersisters.
- In undiagnosed or self-identified lactose-intolerant individuals.
- How does this differ by age and ethnicity?
- Health outcomes to include: Bone health – osteoporosis, fracture, bone density, bone mass; and gastrointestinal symptoms - abdominal pain, diarrhea, nausea, flatulence, bloating.
- What amount of daily lactose intake is tolerable in subjects with diagnosed lactose intolerance?
- How does this differ by age and ethnicity?
- What are the diagnostic standards used?
- What strategies are effective in managing individuals with diagnosed lactose intolerance?
- Commercially available lactase
- Prebiotics and probiotics
- Incremental lactose loads for colonic adaptation
- Other dietary strategies
- What are the future research needs for understanding and managing lactose intolerance?
Appendixes and evidence tables cited in this report are available at http://www
.ahrq.gov/downloads /pub/evidence /pdf/lactoseint/lactint.pdf.
Agency for Healthcare Research and Quality (US), Rockville (MD)
Wilt TJ, Shaukat A, Shamliyan T, et al. Lactose Intolerance and Health. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Feb. (Evidence Reports/Technology Assessments, No. 192.) 1, Introduction.