Pediatric Lactose Intolerance

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Background

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.

Pathophysiology

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.



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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.

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.

Epidemiology

Frequency

United States

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.[2] 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 African Americans 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 recent consensus statement provides an updated overview of the extent of this problem in such populations.[3]

International

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%, while Northern Indians have a much lower prevalence than Southern Indians, at approximately 25% and 65%, respectively. Almost all (90%) Asians and Africans are affected.

Mortality/Morbidity

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.

Race

See Frequency.

Sex

No sex differences in the prevalence of adult-type hypolactasia are known.

Age

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 recent studies have actually shown that hypolactasia may begin even after age 20.[4] 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.

History

Symptoms of lactose intolerance include the following:

Physical

Physical examination may reveal the following:

Causes

Causes include the following:

Laboratory Studies

The following laboratory studies are indicated in patients with lactose intolerance:

Other Tests

Other tests may include the following:

Procedures

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.

Histologic Findings

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.

Medical Care

Treatment of lactose intolerance may include the following:

Consultations

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.

Diet

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.[15]

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.[16]

Medication Summary

Medication is not currently a component of care in this condition. See Treatment.

Complications

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, recently no evidence was found to substantiate the risk of low vitamin D levels in children with lactose intolerance.[17]

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. A recent study addressed this issue and found no evidence that lactose-intolerant children are at risk of short stature.[17]

Calcium supplementation through the administration of dietary or pharmacological supplements is suggested for any child who does not receive adequate calcium.

Patient Education

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).[2]

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:

Author

Stefano Guandalini, MD, Founder and Medical Director, Celiac Disease Center, Chief, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Chicago Medical Center; Professor, Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Division of the Biological Sciences, The 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, 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.

Additional Contributors

Eric S Maller, MD,

Disclosure: Nothing to disclose.

References

  1. Campbell AK, Waud JP, Matthews SB. The molecular basis of lactose intolerance. Sci Prog. 2009. 92:241-87. [View Abstract]
  2. [Guideline] Brannon PM, Carpenter TO, Fernandez JR, et al. NIH Consensus Development Conference Statement: Lactose Intolerance and Health. NIH Consens State Sci Statements. 2010 Feb 24. 27(2):[View Abstract]
  3. Bailey RK, Fileti CP, Keith J, Tropez-Sims S, Price W, Allison-Ottey SD. Lactose intolerance and health disparities among African Americans and Hispanic Americans: an updated consensus statement. J Natl Med Assoc. 2013. 105(2):112-27. [View Abstract]
  4. Seppo L, Tuure T, Korpela R, et al. Can primary hypolactasia manifest itself after the age of 20 years? A two-decade follow-up study. Scand J Gastro. 2008. 43:1082-1087. [View Abstract]
  5. Montalto M, Gallo A, Santoro L, et al. Low-dose lactose in drugs neither increases breath hydrogen excretion nor causes gastrointestinal symptoms. Aliment Pharmacol Ther. 2008 Oct 15. 28(8):1003-12. [View Abstract]
  6. Gijsbers CF, Kneepkens CM, Büller HA. Lactose and fructose malabsorption in children with recurrent abdominal pain: results of double-blinded testing. Acta Paediatr. 2012 Sep. 101(9):e411-5. [View Abstract]
  7. Wilder-Smith CH, Materna A, Wermelinger C, Schuler J. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun. 37(11):1074-83. [View Abstract]
  8. Krawczyk M, Wolska M, Schwartz S, et al. Concordance of genetic and breath tests for lactose intolerance in a tertiary referral centre. J Gastrointestin Liver Dis. 2008 Jun. 17(2):135-9. [View Abstract]
  9. Aragón JJ, Hermida C, Martínez-Costa OH, Sánchez V, Martín I, Sánchez JJ. Noninvasive Diagnosis of Hypolactasia With 4-Galactosylxylose: A Multicentre, Open-Label, Phase IIB-III Nonrandomized Trial. J Clin Gastroenterol. 2013 May 29. [View Abstract]
  10. Hovde O, Farup PG. A comparison of diagnostic tests for lactose malabsorption--which one is the best?. BMC Gastroenterol. 2009 Oct 31. 9:82. [View Abstract]
  11. Marton A, Xue X, Szilagyi A. Meta-analysis: the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/T-13910. Aliment Pharmacol Ther. 2012 Feb. 35(4):429-40. [View Abstract]
  12. Griffin MP, Hansen JW. Can the elimination of lactose from formula improve feeding tolerance in premature infants?. J Pediatr. 1999 Nov. 135(5):587-92. [View Abstract]
  13. Petschow B, Doré J, Hibberd P, Dinan T, Reid G, Blaser M. Probiotics, prebiotics, and the host microbiome: the science of translation. Ann N Y Acad Sci. 2013 Nov 22. [View Abstract]
  14. Lactose intolerance and African Americans: implications for the consumption of appropriate intake levels of key nutrients. J Natl Med Assoc. 2009 Oct. 101(10 Suppl):5S-23S. [View Abstract]
  15. Bacsi K, Kosa JP, Lazary A, et al. LCT 13910 C/T polymorphism, serum calcium, and bone mineral density in postmenopausal women. Osteoporos Int. 2008 Aug 13. [View Abstract]
  16. Medeiros LC, Lederman HM, de Morais MB. Lactose malabsorption, calcium intake, and bone mass in children and adolescents. J Pediatr Gastroenterol Nutr. 2012 Feb. 54(2):204-9. [View Abstract]
  17. Setty-Shah N, Maranda L, Candela N, Fong J, Dahod I, Rogol AD. Lactose intolerance: lack of evidence for short stature or vitamin d deficiency in prepubertal children. PLoS One. 2013. 8(10):e78653. [View Abstract]

The small intestine is a major site of absorption.

The small intestine is a major site of absorption.