Lactase Non-persistence and Lactose Intolerance

  • Theodore M. BaylessEmail author
  • Elizabeth Brown
  • David M. Paige
Small Intestine (D Sachar, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Small Intestine


Purpose of Review

To evaluate the clinical and nutritional significance of genetically determined lactase non-persistence and potential lactose and milk intolerance in 65–70% of the world’s adult population.

Recent Findings

Milk consumption is decreasing in the USA and is the lowest in countries with a high prevalence of lactase non-persistence. The dairy industry and Minnesota investigators have made efforts to minimize the influence of lactose intolerance on milk consumption. Some lactose intolerant individuals, without co-existent irritable bowel syndrome, are able to consume a glass of milk with a meal with no or minor symptoms. The high frequency of lactase persistence in offspring of Northern European countries and in some nomadic African tribes is due to mutations in the promoter of the lactase gene in association with survival advantage of milk drinking.


Educational and commercial efforts to improve calcium and Vitamin D intake have focused on urging consumption of tolerable amounts of milk with a meal, use of lowered lactose-content foods including hard cheeses, yogurt, and lactose-hydrolyzed milk products.


Lactase non-persistence Lactose intolerance Lactase persistence Evolution, positive selection Milk drinking 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This review contains published papers that presumably met journal standards for publication.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Auricchio S, Rubino A, Semenza G, Landolt M, Prader A. Isolated intestinal lactase deficiency in the adult. Lancet. 1963;2(7303):324–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Dahlqvist A, Hammond JB, Crane RK, Dunphy JV, Littman A. Intestinal lactase deficiency and lactose intolerance in adults. Preliminary report. Gastroenterology. 1963 October;45:488–91.PubMedGoogle Scholar
  3. 3.
    •• Bayless TM, Rosensweig NS. A racial difference in incidence of lactase deficiency. JAMA. 1966;197(19):138–42. Second most widely cited gastroenterology paper in JAMA in 50 year period. Reference #4 was the most cited. Google Scholar
  4. 4.
    Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis. A pathologic and clinical entity. JAMA. 1932;99:1323–9.CrossRefGoogle Scholar
  5. 5.
    Cuatrecasas P, Lockwood DH, Caldwell JR. Lactase deficiency in the adult. A common occurrence. Lancet. 1965;1(Jan 2):14–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Ransome-Kuti B. Personal communication. 1996Google Scholar
  7. 7.
    Huang SS, Bayless TM. Milk and lactose intolerance in healthy Orientals. Science. 1968;160(5 April):83–4.CrossRefPubMedGoogle Scholar
  8. 8.
    •• Swallow DM. Genetics of lactase persistence and lactose intolerance. Annu Rev Genet. 2003;37:197–219. A key early review on lactase persistence and non-persistence. CrossRefPubMedGoogle Scholar
  9. 9.
    •• Ingram CJE, Mulcare CA, Itan Y, Thomas MG, Swallow DM. Lactose digestion and the evolutionary genetics of lactase persistence. Hum Genet. 2009;124:579–91. Important review on evolution of lactase persistence. CrossRefPubMedGoogle Scholar
  10. 10.
    •• Simoons FJ. Primary lactose intolerance and the milking habit: a problem in biological and cultural interrelationships. II. A culture historical hypothesis. Am J Dig Dis. 1970;15:695–710. The leader in recognizing the role of dairying and milk consumption in the development of lactase persistence CrossRefPubMedGoogle Scholar
  11. 11.
    Simoons FJ. The geographic hypothesis and lactose malabsorption—a weighing of the evidence. Am J Dig Dis. 1978;23:963–80.CrossRefPubMedGoogle Scholar
  12. 12.
    •• Simoons FJ. Lactose digestion. Clinical and nutritional implications. In: Paige DM, Bayless TM, editors. Geographic patterns of primary adult lactose malabsorption. A further interpretation of evidence for the old world. Baltimore: Johns Hopkins University Press; 1981. p. 23–48. The first text on lactose intolerance.Google Scholar
  13. 13.
    • Jones BL, Oljira T, Liebert A, et al. Diversity of lactase persistence in African milk drinkers. Hum Genet. 2015;134:917–25.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    •• Enattah N, Sahi T, Savilahti E, Terwilliger JD, Groop PH, Jarvela I, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:223–7. Seminal paper on the lactase non-persistence gene. CrossRefGoogle Scholar
  15. 15.
    Poulter M, Hollox E, Harvey CB, et al. The causal element for the lactase persistence/non-persistence polymorphism is located in a 1Mb region of linkage disequilibrium in Europeans. Ann Hum Genet. 2003;67:298–311.CrossRefPubMedGoogle Scholar
  16. 16.
    Troelsen JT. Adult-type hypolactasia and regulation of lactase expression. Biochim Biophys Acta. 2005;1723:19–32.CrossRefPubMedGoogle Scholar
  17. 17.
    Jarvela I, Torniainen S, Kolho KL. Molecular genetics of human laccase deficiencies. Ann Med. 2009;41:568–75.CrossRefPubMedGoogle Scholar
  18. 18.
    • Dzialanski Z, Barany M, Engfeldt MA, Olsson LA, Nilsson TK. Lactase persistence versus lactose intolerance: is there an intermediate phenotype? Clinbiochem. 2016;49:248–52. Describes heterozygotes.Google Scholar
  19. 19.
    Ennattah ND, Kuokkanen M, Forsblom C, et al. Correlation of intestinal disaccharidase activities with the C/T-13910 variant and age. World J Gastroenterol. 2007;12:3508–12.CrossRefGoogle Scholar
  20. 20.
    • Santonocita C, Scapaticci M, Guarino D, et al. Lactose intolerance genetic testing: is it useful as routine screening? Results on 1426 south-central Italy patients. Clinical Chimica Acta. 2015;439:14–7. Used commercial kit to determine lactase status.CrossRefGoogle Scholar
  21. 21.
    • Awuah B, Yaa N, Fleet S, et al. Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patents and evidence for a novel lactase persistence allele at -13909 in those of European ancestry. J Pediatr Gastroenterol Nutr. 2015;60:182–91. Useful study from Boston Pediatrics.CrossRefGoogle Scholar
  22. 22.
    • Labrie V, Burke OJ, Oh E, et al. Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging. Nat Struct Mol Biol. 2016;23:566–73. Proposes epigenetic aging to explain lactase non-persistence. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    •• Szilagyi A. Adult lactose digestion status and effects on disease. Can J Gastroenterol Hepatol. 2015a;29:149–56. Important review. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    •• Szilagyi A, Galiatsatos P, Xue X. Systematic review and meta-analysis of lactose digestion, its impact on intolerance and nutritional effects of dairy food restriction in inflammatory bowel diseases. Nutr J. 2016;15:67–80. Useful review. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    • Levitt M, Witt T, Shaukat A. Clinical implications of lactose malabsorption versus lactose intolerance. J Clin Gastro. 2013;47:471–80. Reviews placebo controlled trials and tends to minimize the clinical importance of lactose intolerance. CrossRefGoogle Scholar
  26. 26.
    • Raz M, Sharon Y, Yerushalmi B, Birk R. Frequency of LCT-13910C/T and LCT-22018G/A single nucleotide polymorphisms associated with adult-type hypolactasia/lactase persistence among Israelis of different ethnic groups. Gene. 2013;519:67–70. Good ethnic study. CrossRefPubMedGoogle Scholar
  27. 27.
    •• Paige DM. Lactose intolerance. Encyclopedia of Human Nutrition (Third Edition). 2013:67–73. An excellent review of the nutritional implications.Google Scholar
  28. 28.
    •• Curry A. Archaeology: the milk revolution. When a single genetic mutation first let ancient Europeans drink milk, it set the stage for a continental upheaval. Nature. 2013;50:20–2. Great story, with maps, of the evolution of lactase persistence and milk drinking. CrossRefGoogle Scholar
  29. 29.
    •• Silanikove N, Leitner G, Merin U. The interrelationships between lactose intolerance and the modern dairy industry: global perspectives in evolutional and historical backgrounds. Nutrients. 2015a;7:7312–31. Excellent global perspective on the dairy industry.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    • Gerbault P. The onset of lactase persistence in Europe. Hum Hered. 2013;76:154–161.1. An anthropological perspective.CrossRefPubMedGoogle Scholar
  31. 31.
    • Diekmann L, Pfeiffer K, Naim HY. Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. BMC Gastroenterol. 2015;16:36–43. Congenital lactase deficiency.CrossRefGoogle Scholar
  32. 32.
    Elliott RB, Maxwell GM, Vawser N. Lactose maldigestion in Australian aboriginal children. Med J Aust. 1967;1:46–9.PubMedGoogle Scholar
  33. 33.
    Huang SS, Bayless TM. Lactose intolerance in healthy children. New Engl J Med. 1967;276:1283–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Paige DM, Bayless TM, Mellits ED, Davis L. Lactose malabsorption in preschool black children. Am J Clin Nutr. 1977;30:1018–22.PubMedGoogle Scholar
  35. 35.
    Bayless TM, Huang SS. Recurrent abdominal pain due to milk and lactose intolerance in school-aged children. Pediatrics. 1971;47:1029–32.PubMedGoogle Scholar
  36. 36.
    Wittenberg DF, Moosa A. Lactose maldigestion-age-specific prevalence in black and Indian children. S Afr Med J. 1990;78:470–2.PubMedGoogle Scholar
  37. 37.
    Thomas S, Walker-Smith JA, Senewiratne B, Hjelm M. Age dependency of the lactase persistence and lactase restriction phenotypes among children in Sri Lanka and Britain. J Trop Peditr. 1990;30:80–5.CrossRefGoogle Scholar
  38. 38.
    Kuchay RAH, Thapa BR, Mahmod A, Mahmood S. Effect of C/T-13910 cos-acting regulatory variant on expression and activity of lactase in Indian children and its implication for early genetic screening of adult-type hypolactasia. Clin Chim Acta. 2011;412:1924–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Rossi M, Maiuri L, Fusco MI, et al. Lactase persistence versus decline in human adults: multifactorial events are involved in down-regulation after weaning. Gastroenterology. 1997;112:1506–14.CrossRefPubMedGoogle Scholar
  40. 40.
    •• Bayless TM, Christopher NL, Boyer SH. Autosomal recessive inheritance of intestinal lactase deficiency: evidence from ethnic differences. J Clin Invest. 1969:48–6a. Described lactase deficiency as a recessive trait. Google Scholar
  41. 41.
    Sahi T, Isokoski M, Jussila J, Launiala K, Pyorala K. Recessive inheritance of adult-type lactose malabsorption. Lancet. 1973;2:823–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Metneki J, Czeizel A, Flatz S, Flatz G. A study of lactose absorption capacity in twins. Hum Genet. 1984;67:296–300.CrossRefPubMedGoogle Scholar
  43. 43.
    • Paz-y-Mino C, Burgos G, Lopez-Cortes A, et al. A study of the molecular variants associated with lactase persistence in different Ecuadorian ethnic groups. Am J Human Biol. 2016;0:1–11. Shows effects of genetic admixture on lactase polymorphism.Google Scholar
  44. 44.
    Suarez FI, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med. 1995;333:1–4.CrossRefPubMedGoogle Scholar
  45. 45.
    •• Yang J, Deng Y, Chu H, et al. Prevalence and presentation of lactose intolerance and effects on dairy product intake in healthy subjects and patients with irritable bowel syndrome. Clin Gastro Hepatol. 2013;11:262–8. A good study of the role of co-existent IBS in a population with universal lactase non-persistence. CrossRefGoogle Scholar
  46. 46.
    Christopher NL, Bayless TM. Role of the small bowel and colon in lactose-induced diarrhea. Gastroenterology. 1971;60:845–52.PubMedGoogle Scholar
  47. 47.
    Bedine MS, Bayless TM. Intolerance of small amounts of lactose by individuals with low lactose levels. Gastroenterology. 1973;65:735–43.PubMedGoogle Scholar
  48. 48.
    • Deng Y, Misselwitz DN, Fox M. Lactose intolerance in adults: biological mechanism and dietary management. Nutrients. 2015;7:8020–35. A broad review.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mitchell KJ, Bayless TM, Paige DM, Goodgame RW, Huang SS. Intolerance of eight ounces of milk in healthy lactose-intolerant teen-agers. Pediatrics. 1975;56:718–21.PubMedGoogle Scholar
  50. 50.
    Bayless TM, Rothfeld B, Massa C, Wise L, Paige D, Bedine MS. Lactose and milk intolerance: clinical implications. N Engl J Med. 1975;292:156–9.CrossRefGoogle Scholar
  51. 51.
    •• Shaukat A, Levitt MD, Taylor BC, MacDonald R, Shamilyan TA, Kane RL, Witt TJ. Systematic review: effective management strategies for lactose intolerance. Ann Intern Med. 2010;152:797–803. Reviews placebo controlled trials and tends to minimize the clinical importance of lactose intolerance. CrossRefPubMedGoogle Scholar
  52. 52.
    •• Suchy GJ, Brannon PM, Carpenter TO, et al. National Institutes of Health consensus development conference: lactose intolerance and health. Ann Intern Med. 2010;152:792–6. Reviews placebo controlled trials and tends to minimize the clinical importance of lactose intolerance. CrossRefPubMedGoogle Scholar
  53. 53.
    •• Erickson J, Sadeghirad B, Lytyvn L, Slavin J, Johnston BC. The scientific basis of guideline recommendations on sugar intake: A systematic review. Ann Intern Med 2016; Dec 20. Doi  10.7326/M16-2020. A highly criticized attempt by the sugar industry to minimize the importance of sugar in obesity be altering definitions and selecting biased studies, reminiscent of the efforts by the tobacco and dairy industries.
  54. 54.
    Paige, DM & Graham, GG, "Nutritional Implications of Lactose Malabsorption", Pediatric Research abstract 6:329, 1972.Google Scholar
  55. 55.
    Paige, DM, Bayless, TM, and Graham, GG, "Pregnancy and Lactose Intolerance," American Journal of Clinical Nutrition, 26:238–240, March, 1973.Google Scholar
  56. 56.
    Leichter, J, "Effects of Lactose on the Absorption of Other Nutrients" in Paige, DM, & Bayless, TM, Editors: "Lactose Digestion: Clinical and Nutritional Implications", The Johns Hopkins University Press, Baltimore, Maryland, P.142–147,1981.Google Scholar
  57. 57.
    •• Paige DM, Bayless TM, Huang SS, Wexler R. Lactose hydrolyzed milk. Am J Clin Nutr. 1975;28:818–22. First report of lactose hydrolyzed milk being acceptable for lactose intolerant individuals. PubMedGoogle Scholar
  58. 58.
    • Casellas F, Aparici A, Perez MJ, Rodriguez P. Perception of lactose intolerance impairs health-related quality of life. European J Clin Nutr. 2016;70:1068–72. Overlap with IBS a problem. CrossRefGoogle Scholar
  59. 59.
    • Szilagyi A. Adaptation to lactose in lactase non persistent people: effects on intolerance and the relationship between dairy food consumption and evaluation of diseases. Nutrients. 2015b;7:6751–79. An important look at dairy food consumption and adaptation to continued small amounts of lactose. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Hertzler SR, Savaiano DA, Levitt MD. Fecal hydrogen production and consumption measurements. Response to daily lactose ingestion by lactose maldigesters. Dig Dis Sci. 1997;42:348–53.CrossRefPubMedGoogle Scholar
  61. 61.
    •• Briet F, Pochart P, Marteau P, Flourie B, Arrigoni E, Rambaud JC. Improved clinical tolerance to chronic lactose ingestion in subjects with lactose intolerance: a placebo effect? Gut. 1997;41:632–5. Poor paper. Used 50 grams of lactose, equivalent to a quart of milk, as the challenge! CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    • Bohner CJ, Tuynman HA. The effect of a lactose-restricted diet in patients with a positive lactose tolerance test, earlier diagnosed as irritable bowel syndrome: a 5-year follow-up study. Eur J Gastroenterol Hepatol. 2001;13:941–4. A good early study of the role of lactose intolerance in some patients with IBS. CrossRefGoogle Scholar
  63. 63.
    Zhu Y, Zheng X, Cong Y, Chu H, Fried M, Dai N, Fox M. Bloating and distention in irritable bowel syndrome: the role of gas production and visceral sensation after lactose ingestion is a population with lactase deficiency. Am J Gastroenterol. 2013;10:1516–25. A good pathophysiologic study of the reasons for exaggerated symptoms of lactose intolerance in subjects with co-existent IBS. CrossRefGoogle Scholar
  64. 64.
    • Arguelles-Arias F, Rodriguez-Ledo, Tenias JM et al. The management of lactose intolerance among primary care physicians and its correlation with management by gastroenterologists: the SEPD=SEMG national survey. Rev Esp Enfirm Dig (Madrid) 2015;107:554–559. Spanish gastroenterologists considered lactose intolerance a minor condition and saw it as overlapping with IBS. Google Scholar
  65. 65.
    • Ferdman RA. The mysterious case of America’s plummeting milk consumption. The Washington Post June 20.2014. A reporter’s view of milk consumption.Google Scholar
  66. 66.
    • Sebastian RD, Goldman JD, Wilkinson Enns C, LaComb, RP. Fluid milk consumption in the United States: What we eat in America. NHANES 2005–2006. Food Surveys Research Group. Dietary Data Brief No.3. Sept 2010. Major data on milk consumption from the government.Google Scholar
  67. 67.
    •• Shrier I, Szilagyi A, Correa JA. Impact of lactose containing foods and the genetics of lactase on diseases: an analytical review of population data. Nut Cancer. 2008;60:292–300. Shows prevalence of lactase non-persistence in a country’s population correlates with the amount of dairy food consumption. CrossRefGoogle Scholar
  68. 68.
    Paige DM, Bayless TM, Ferry GD, Graham GG. Lactose malabsorption and milk rejection in Negro children. Johns Hopkins Med J. 1971;20:163–70.Google Scholar
  69. 69.
    Paige DM, Bayless TM, Graham GG. Milk programs: helpful of harmful to Negro children? Am J Pub Health. 1972;62:486–8.Google Scholar
  70. 70.
    • Almon R, Sjostrom M, Nillsson TK. Lactase non-persistence as a determinant of milk avoidance and calcium intake in children and adolescents. J Nutr Sci. 2013;2:e26. doi: 10.1017/jns2013.11.Linked LMP and decreased dairy intake.
  71. 71.
    Keith JN, Nicholls J, Reed A, Kafer K, Miller GD. The prevalence of self-reported lactose intolerance and the consumption of dairy foods among African American adults are less than expected. J Natl Med Assoc. 2011;102:36–45.CrossRefGoogle Scholar
  72. 72.
    • Baadkar SV, Mukherjee MS, Lele SS. Study on influence of age, gender and genetic variants on lactose intolerance and its impact on milk intake in adult Asian Indians. Hum Biol. 2014;41:548–53. Linked LMP and diminished dairy ingestion.Google Scholar
  73. 73.
    Paige DM, Witter FR, Bronner YL, Kessler LA, Perman JA, Paige TR. Lactose digestion in pregnant African-Americans. Pub Health Nutr. 2003;6:801–7.CrossRefGoogle Scholar
  74. 74.
    • Bailey RK, Fileli CP, Keith J, Tropez-Sims S, Price W, Allison-Offey SD. Lactose intolerance and health disparities among African Americans and Hispanic Americans: an updated consensus statement. J Natl Med Assoc. 2013;105:112–27. Funded by National Dairy Association. CrossRefPubMedGoogle Scholar
  75. 75.
    • Heaney RP. Dairy intake, dietary adequacy and lactose intolerance. Adv Nutr. 2013;4:151–60. Concern for decreased dairy intake and relation to lactose intolerance.Google Scholar
  76. 76.
    • Brown-Riggs C. Nutrition and health disparities: the role of dairy in improving minority health outcomes. Int J Environ Res Public Health. 2016;13:28–36. Supports the use of yogurt in lactose intolerant populations. CrossRefGoogle Scholar
  77. 77.
    • Opstelten JL, Leenders M, Dik VK, et al. Dairy products, dietary calcium and risk of inflammatory bowel disease: results from a European prospective cohort investigation. Inflam Bowel Dis/. 2016;22:1402–11. Risk of dietary calcium inadequacy in Inflammatory Bowel Disease Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Theodore M. Bayless
    • 1
    • 2
    Email author
  • Elizabeth Brown
    • 3
  • David M. Paige
    • 3
  1. 1.Meyerhoff Digestive Diseases-Inflammatory Bowel Disease Center, Gastroenterology DivisionJohns Hopkins University School of Medicine, Johns Hopkins HospitalBaltimoreUSA
  2. 2.TowsonUSA
  3. 3.Department of Population, Family and Reproductive HealthJohns Hopkins University, Bloomberg School of Public HealthBaltimoreUSA

Personalised recommendations