Lactose intolerance in adulthood is very common and is the result of a genetically programmed progressive loss of the activity of the small intestinal enzyme lactase. Some scientists believe that human adult lactase polymorphism evolved in the Neolithic period, after animal milk became available for the nutrition of older children and adults. Expression of the lactase enzyme starts to decline in most persons at age 2 years; almost 4 billion people worldwide have lactose malabsorption. However, symptoms of lactose intolerance rarely develop in people younger than 6 years.
Milk intolerance is more frequently due to milk-protein allergy than primary lactase deficiency. Although transient lactose intolerance may occur during acute gastroenteritis and as part of any process that leads to reduction of the small intestinal absorptive surface (such as untreated celiac disease), it is rarely clinically significant and, when present, can be easily treated with a short course of a lactose-free diet. Diagnosing lactose intolerance based on symptoms is fairly inaccurate; however, self-reported symptoms of lactose intolerance correlate with low calcium intake. Calcium supplementation should accompany any restriction of milk products.
Usually, very little morbidity is associated with lactase deficiency. Transient lactase deficiency affects a significant number of infants with severe gastroenteritis and diarrhea. Symptoms generally resolve within 5-7 days.
Lactose, a disaccharide unique to mammalian milk, is hydrolyzed into the monosaccharides glucose and galactose at the brush border of enterocytes on the villous tip by the enzyme lactase (a beta-D-galactosidase known as lactase phlorizin hydrolase).
Lactose appears to enhance the absorption of several minerals, including calcium, magnesium, and zinc. The small intestine is a major site of absorption and is illustrated in the image below.
View Image
The small intestine is a major site of absorption.
It also promotes the colonic growth of Bifidobacterium and is the source of galactose, which is an essential nutrient for the formation of cerebral galactolipids. The gene for lactase is located on chromosome 2. Hypolactasia seems to be strongly correlated with genotype C/C of the genetic variant C-->T(-13910) upstream of the lactase phlorizin hydrolase gene.
The molecular bases of lactose intolerance have been reviewed.[1]
Human and animal studies suggest that numerous modulators result in variable expression of lactase at different ages. Thyroxine may promote the decline in lactase enzyme expression that appears in childhood, whereas hydrocortisone appears to increase lactase levels. Although premature infants have partial lactase deficiency because of intestinal immaturity, enzyme expression can be induced by lactose ingestion. Improvement of lactose digestion in a previously intolerant child or adult is caused by growth of lactose-digesting bacteria rather than an induction in activity of the lactase enzyme because lactase is a noninducible enzyme.
A 2023 in vitro study that evaluated the impact of lactose on healthy adult gut microbiota by anaerobically culturing fecal samples with and without lactose from 18 donors found that samples with lactose added reduced richness and evenness but enhanced the prevalence of the beta-galactosidase gene.[2] The relative abundance of Bacteroidaceae fell in the lactose-treated samples, whereas levels of lactic acid bacteria (Lactobacillaceae, Enterococcaceae, Streptococcaceae) and the probiotic Bifidobacterium rose. These changes were associated with a rise in Veillonellaceae, which are lactate utilizers. Moreover, there was an increase in total short-chain fatty acids (acetate, lactate).[2]
Congenital lactase deficiency is an extremely rare autosomal recessive disorder associated with a complete absence of lactase expression. Childhood-onset and adult-onset lactase deficiency are extremely common and are inherited in an autosomal recessive manner. The CC genotype of the 13910 C/T polymorphism of the LCT gene is linked to such late-onset primary hypolactasia. Persistent lactase activity into adulthood is inherited in an autosomal dominant manner. Acquired lactase deficiency, which is a transient phenomenon by definition, is due to damage of the intestinal mucosa by an infectious, allergic, or inflammatory process and resolves once the disease process is corrected and healing of the intestinal mucosa restores the brush border enzymes.
This is caused by a low or absent activity of the enzyme lactase.
Adult-onset lactose intolerance
This deficiency results from an unusual mechanism that involves a developmentally regulated change of the lactase gene product, resulting in a reduced synthesis of the precursor protein. Differences in the rate of gene transcription account for much of the differences in lactose intolerance observed among racial groups.
Low lactase activity in the small intestine
This allows undigested lactose to pass into the colon. In the colon, bacteria ferment the sugar to hydrogen gas and organic acids. The gas produces distention of the bowel, creating the sensation of bloating, cramping, and abdominal pain. Organic acids can be absorbed, but the quantity produced is rarely large enough to cause systemic symptoms or metabolic acidosis.
Although as many as 20-25% of White US adults are believed to be lactase deficient, the true prevalence of this condition is unknown, as noted in a comprehensive National Institute of Health (NIH) consensus conference on the topic.[3] The prevalence in other racial groups parallels the country of racial origin. Symptomatic individuals represent only about 50% of lactase deficiency cases.
On average, both Black and Hispanic Americans consume less than the recommended levels of dairy foods, and perceived or actual lactose intolerance can be a primary reason for limiting or avoiding dairy intake, while true lactose intolerance prevalence is not known in these populations. A consensus statement provides an updated overview of the extent of this problem in such populations.[4]
International data
An estimated 68-70% of the global population has lactose intolerance.[5] Adult-onset lactase deficiency varies widely among countries. Northern Europeans have the lowest prevalence at approximately 5%. Central Europeans have a higher prevalence at approximately 30%, and Southern Europeans have a much higher prevalence at approximately 70%. Hispanic and Jewish populations also have a high prevalence at approximately 70%, whereas Northern Indians have a much lower prevalence than Southern Indians, at approximately 25% and 65%, respectively. Almost all (90%) Asians and Africans are affected.
A systematic review and meta-analysis of the MEDLINE and Embase literature from inception to late 2016 comprising data from 450 study populations (N = 62,910) and 89 countries of individuals at least 10 years old found an estimated 68% global prevalence of lactose malabsorption (standardized for country size).[6] In Western, Southern, and Northern Europe, it was 28%, whereas in the Middle East it was 70%. Using genotyping data, the estimate of global prevalence was 74%; using lactose tolerance test data, it was 55%; and using hydrogen breath test date, it was 57%.[6]
Sex and age-related demographics
No sex differences in the prevalence of adult-type hypolactasia are known.
Lactase activity in the fetal intestine progressively increases through the third trimester and approaches maximum expression at term. Preterm infants have diminished levels of lactase. Few infants born at 28 weeks' gestation have significant intestinal lactase activity, whereas approximately 40% of infants born at 34 weeks' gestation demonstrate significant intestinal lactase activity. The premature neonatal period is the only time in which lactase enzyme production and expression can be induced. Because congenital lactase deficiency is exceedingly rare, diagnoses such as glucose-galactose malabsorption or the much more common milk-protein allergy should be considered in an infant with symptoms of milk or milk-based formula intolerance.
Lactase activity is genetically programmed to decline, beginning after age 2 years. Signs and symptoms usually do not become apparent until after age 6-7 years, and relatively recent studies have actually shown that hypolactasia may begin even after age 20.[7] Symptoms, therefore, may not be apparent until adulthood, depending on dietary lactose intake and rate of decline of intestinal lactase activity. Lactase enzyme activity is highly correlated with age, regardless of symptoms.
Secondary lactase deficiency due to intestinal mucosal injury can appear at any age; however, children younger than 2 years are very susceptible because of many factors, including a high sensitivity of the gut to infectious agents, low reserve because of the small intestinal surface area, and high reliance on milk-based products for nutrition.
Lower calcium levels are found in individuals with lactose intolerance; thus, emphasizing the importance of calcium supplementation is important. Again, despite lactose malabsorption, adults with lactose intolerance are able to tolerate substantial amounts of lactose-containing dairy products, such as milk (and even more yogurts).[3]
Although the symptoms are directly related to the quantity of lactose ingested, the patient should be educated about the fact that lactose may be hidden, in low amounts, in the following foods:
Breads
Baked goods
Cereals
Instant mixes
Margarine
Dressings
Candies
Snacks
Some over-the-counter drugs can reduce symptoms (eg, simethicone for relief of flatulence, exogenous lactase drops or tablets derived from yeast)
Bloating, abdominal discomfort, meteorism, and flatulence that occur from 1 hour to a few hours after ingestion of milk or dairy products may signify lactose intolerance; however, other disorders such as milk-protein sensitivity, allergic-type reactions to other substances in the meal, or other saccharide intolerance may cause similar symptoms.
Many individuals with lactose intolerance are concerned about the presence of lactose in many orally administered drugs; however, one investigation concluded that no side effects are experienced by adults with hypolactasia upon ingestion of lactose-containing drugs.[8]
Adults and adolescents who have been diagnosed with lactose malabsorption appear able to tolerate as much as 12 g of lactose in a single dose (equivalent to the lactose content found in 1 cup of milk). Even larger amounts can be tolerated if they are ingested with meals and distributed throughout the day. However, 50 g of lactose (the lactose content found in 1 quart of milk) usually causes symptoms in adults with lactose malabsorption when administered as a single dose outside of meals.[3]
Although lactose intolerance is often suspected in children with functional recurrent abdominal pain, strong evidence suggests that lactose intolerance plays no role in such condition.[9]
Of note, although lactose (as well as fructose) intolerance is associated with gastrointestinal symptoms, the relationship of lactose malabsorption with symptoms in patients with functional gastrointestinal disorders is not clear.[10]
Associated food
The rate of gastric emptying is important in the development of symptoms, which may develop if lactose moves quickly to an intestine that is low in lactase. Fats decrease the rate of gastric emptying, whereas carbohydrates increase the rate of gastric emptying. Thus, if dairy products that contain lactose are ingested with carbohydrates, especially simple carbohydrates, symptoms are more likely.
Allergies to food proteins, particularly milk and grain proteins, can mimic lactose intolerance in part.
Inflammation of the intestinal mucosa due to infection or protein-sensitive enteritis causes secondary lactose intolerance.
Stool characteristics
Loose, watery, acidic stool often with excessive flatus and associated with urgency that occurs a few hours after the ingestion of lactose-containing substances is typical.
Gastroenteritis
Infectious diarrhea, particularly viral gastroenteritis in younger children, may damage the intestinal mucosa enough to reduce the quantity of the lactase enzyme. This does not result in any significant problem and does not require any changes in formula. However, intolerance is rarely more evident, especially in malnourished infants, and requires a few days of lactose-free feedings. Abundant literature conclusively shows that breastfeeding can and should always be continued throughout an episode of gastroenteritis, despite the high content of lactose in breast milk.
Food avoidance
Many people with lactose intolerance instinctively avoid products that contain lactose.
Nonspecific, nonfocal abdominal pain and cramping are common and are sometimes associated with bloating and flatus. This pain may mildly increase with palpation. Focal abdominal pain significantly worsened by palpation, the presence of rebound tenderness, or guarding should alert the clinician to a more serious and possibly surgical GI diagnosis.
Borborygmi
A significant increase in peristaltic activity in the small bowel can cause an audible or palpable increase in bowel activity.
Laboratory studies indicated in patients with lactose intolerance are discussed below.
Blood testing
The adult-type hypolactasia (most commonly caused by the CC genotype of the 13910 C/T polymorphism of the LCT gene) can now be easily diagnosed by a genetic analysis. It should, however, be noticed that the presence of the lactase nonpersistent gene does not imply the simultaneous presence of lactose intolerance that may appear later in the life of the subject.
Studies have determined that genetic test results and breath test results are well-correlated, thereby eliminating the need for such testing.[11]
A test based on the measurement of D-xylose after lactase cleavage of orally administered 4-galactosylxylose (Gaxilose) has been investigated in a large multicenter study in adults, with very good sensitivity and specificity for lactase deficiency as measured in biopsy specimens.[12]
Stool analysis
Reducing substances in the stool indicate that carbohydrates are not being absorbed. One common mistake, especially with super-absorbent diapers, is to test the solid portion of the stool instead of the liquid portion.
Acidic stool is defined by a pH level of less than 5.5. This is an indication of likely carbohydrate malabsorption, even in the absence of reducing substances.
Resolution of diarrhea and symptoms when a suspected substance is removed from the diet, as well as resumption of the diarrhea and symptoms when the substance is reintroduced, are very suggestive signs of intolerance.
Lack of diarrhea resolution when a substance is removed from the diet does not necessarily indicate tolerance. Malabsorption of one dietary component can result in diarrhea and subsequent malabsorption of other dietary components; thus, the sensitivity of this procedure can be low.
Conversely, resolution of symptoms upon withdrawal of lactose-containing foods from the diet may not confirm lactose intolerance. For instance, in the case of milk products, a patient can be sensitive to the milk proteins, and symptoms of such an allergy resolve once the milk or milk product is withdrawn from the diet.
Hydrogen breath test
Carbohydrate malabsorption results in bacterial fermentation of the unabsorbed sugar. This biochemical process releases hydrogen gas that is absorbed into the blood and excreted by the lungs. In the absence of hydrolysis of lactose into its component monosaccharide sugars, galactose and glucose, lactose cannot be absorbed and passes into the large intestine. Thus, carbohydrate malabsorption can be determined by measuring the exhaled hydrogen concentration after a carbohydrate load is administered.
Under normal conditions, the fermenting bacteria reside only in the large intestine. When bacterial overgrowth in the small intestine occurs, upper small bowel fermentation of ingested but nonhydrolyzed lactose occurs and causes an early rise in the exhaled hydrogen concentration (>20 ppm). Under such conditions, an additional later rise in exhaled hydrogen occurs during large bowel fermentation.
Antibiotic administration may cause false-negative results. For diagnosis of lactose intolerance, 0.5-1 g/kg to 12-25 g of lactose is administered.
A trial on 60 subjects suspected of lactose malabsorption compared different breath tests and concluded that there was unsatisfactory agreement between commonly used diagnostic tests.[13] The test with the best diagnostic properties was lactose breath test with 25 g lactose and measurement of the increase in the sum of H2 and CH4x2.
A meta-analysis comparing the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests found that overall sensitivity was 0.88 (confidence interval [CI], 0.85-0.90) and specificity was 0.85 (CI, 0.82-0.87) for the breath test. The lactose tolerance test showed sensitivity of 0.94 (CI, 0.9-0.97) and specificity of 0.90 (CI, 0.84-0.95).[14]
Histology
No abnormal histologic findings in the small intestinal mucosa are present in adult-type lactose intolerance and the exceedingly rare primary lactase deficiency. Villous blunting and lamina propria inflammatory changes are seen in cases of secondary lactase deficiency.
Mucosal biopsy is almost never needed to diagnose lactose intolerance. However, it may prove useful as a part of the workup in patients with malabsorption of obscure cause. A small intestinal mucosal biopsy sample is obtained via endoscopy for direct assay of lactase activity and other brush border disaccharidases.
The presence of small intestinal mucosal injury can also be assessed as a possible cause of secondary lactase deficiency.
Treatment of lactose intolerance may include, but are not limited to managing lactase deficiency and lactose intolerance, as well as the use of dietary aids. Medication is not currently a component of care in this condition.
Consultation with a pediatric gastroenterologist is suggested if the patient has symptoms that do not resolve after dietary elimination of lactose or if the patient has severe symptoms.
Lactase deficiency
The lactase enzyme expression can be induced by lactose, but only during the newborn period. Studies demonstrate the use of inducing lactase activity by tube feedings with milk-containing lactose in premature infants. Early initiation of half-strength lactose-containing formula or breast milk results in rapid induction of lactase activity in the brush border and less feeding intolerance. One study suggested that full-strength lactose formula resulted in more feeding intolerance than low-lactose formula in premature infants;[15] thus, the precise lactose concentration of lactose for inducing lactase activity is still undetermined.
Lactose intolerance
This can be improved by dietary manipulation. If the quantity of lactose is increased slowly over time, lactobacilli are stimulated to grow in the colon. A greater number of lactobacilli allow the lactose to break down into monosaccharides. Although this allows much of the sugar to be absorbed, some of the resulting monosaccharides are still fermented by colonic bacteria; however, the relative amount of colonic fermentation is decreased.
Dietary aids
Lactase derived from yeast can be added to milk products as drops or ingested as chewable tablets prior to ingestion of lactose-containing substances. Studies demonstrate varying success. Digestive supplementations are apparently limited in their ability to digest large quantities of lactose.
Yogurt with live cultures is generally well tolerated by individuals with lactose intolerance. Dairy products with reduced or no lactose are widely available.
In addition, research is ongoing that is evaluating the clinical effects of feeding a highly purified, short-chain galactooligosaccharide (GOS/RP-G28) on lactose intolerance and changes in the composition of the colonic microbiota.[16] Intolerant adults fed this sugar showed major changes in their intestinal microbiota, and this was associated with improvement in lactose digestion and overall symptoms of lactose intolerance.
The risks of drastically limiting or excluding all dairy products in populations such as blacks, who may be at risk for nutritional deficiencies, have been illustrated.[17] The importance of maintaining a good intake of dairy products in the face of lactose intolerance has been stressed.[17]
There has been an increase in alternative beverages on the market that mimic dairy foods; these are generally made from pulses, oilseeds, cereals and pseudocereals, as well as seeds.[5] Germination and fermentation, addition of ingredients and/or nutrients, and emerging technologies are being used to ameliorate negative aspects such as sensory, nutritional, and technological limitations in the ingestion and production of these vegetable beverages and dairy analogues.[5]
Lactose is believed to enhance the absorption of several minerals, including calcium, magnesium, and zinc. In addition, milk products that contain a large amount of lactose also contain a high amount of calcium. Because calcium is extremely important in bone growth, children can quickly become deficient if adequate calcium intake is not maintained; thus, calcium supplementation is required in anyone restricted from dairy products. In fact, primary adult hypolactasia has been associated with decreased serum calcium level and lower bone mineral density in postmenopausal women.[18]
In children and teenagers, however, there is less evidence that those who are lactose intolerant are at risk of low calcium intake or bone mineralization. In fact, a study on 76 children and adolescents found no statistically significant difference between the groups (lactose malabsorbers and lactose absorbers) with respect to the intake of total calcium, milk calcium, milk, cheese, yogurt, ice cream, and calcium density of the diet. Additionally, there was no difference with respect to the bone mineral content and the bone mineral density of the lumbar spine.[19]
Milk is the primary source of calcium for children. Children who are lactose intolerant and do not ingest proper quantities of dairy products quickly become depleted of calcium, which places them at risk for rickets and osteomalacia. However, Setty-Shah et al found no evidence to substantiate the risk of low vitamin D levels in children with lactose intolerance.[20]
A controversial area is whether lactose intolerance is associated with short stature. Although some investigators have suggested that adequate calcium intake during the growth period may be critical for reaching optimal bone growth during the growing years, others have provided evidence of short stature in children with lactose intolerance, milk allergy, or those on milk-elimination diets. Setty-Shah addressed this issue and found no evidence that lactose-intolerant children are at risk of short stature.[20]
Calcium supplementation through the administration of dietary or pharmacological supplements is suggested for any child who does not receive adequate calcium.
Stefano Guandalini, MD, AGAF, Founder and Director Emeritus, Celiac Disease Center, University of Chicago; Former Chief, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Chicago Medicine; Professor Emeritus, The University of Chicago Pritzker School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Delia M Rivera, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Disease and Immunology, University of Miami Leonard M Miller School of Medicine
Disclosure: Nothing to disclose.
Richard E Frye, MD, PhD, Professor of Child Health, University of Arizona College of Medicine at Phoenix; Chief of Neurodevelopmental Disorders, Director of Autism and Down Syndrome and Fragile X Programs, Division of Neurodevelopmental Disorders, Department of Neurology, Barrow Neurological Institute at Phoenix Children's Hospital
Disclosure: Nothing to disclose.
Stephen M Borowitz, MD, Professor of Pediatrics and Public Health Sciences, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Virginia School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
B UK Li, MD, Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin; Attending Gastroenterologist, Director, Cyclic Vomiting Program, Children’s Hospital of Wisconsin
Disclosure: Nothing to disclose.
Chief Editor
Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.
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