Lactose Intolerance (Lactase Non-Persistence)

Lactose intolerance is a deficit in the ability to digest lactose, and is due to a relative lack of the lactase enzyme in the small intestine.

Milk is rich in lactose (roughly 40 grams/liter for cow's milk), which serves as the major carbohydrate energy source for infants and young animals. However, dietary lactose cannot be absorbed intact. Rather, it must be hydrolyzed into its constituent monosaccharides glucose and galactose to allow transport across the epithelium. This hydrolysis is dependent upon lactase, a brush border enzyme in epithelial cells in the small intestine.

Developmental Changes in Lactase Expression

In mammals, the normal course of events is for the newborn to subsist on milk over the first few months of life, then be weaned and rarely if ever consume milk again. It thus makes perfect sense that mammals have evolved a developmental pattern of small intestinal gene expression that promotes high level production of lactase early in life, followed by a turnoff of lactase expression around the time of weaning. This is indeed what happens in almost all mammals, including most humans.

A large majority of humans show the typical loss of lactase expression early in life. This downward progression begins at 2 to 3 years of age and is generally complete by 5 to 10 years. Thus, most teenagers and adults have minimal quantities of lactase in their small intestine, and are unable to digest all by a small amount of lactose - they are lactose intolerant and are said to have the trait of lactase non-persistence.

Some humans do not turn off lactase expression during childhood, and continue to produce considerably quanities of the enzyme into adulthood. This trait is called lactase persistence and allows those individuals to tolerate consumption of lactose sources, including milk.

Different populations of humans have different frequencies of the two lactase expression phenotypes. In general:

• Lactase persistence (lactose tolerance) is seen predominantly in individuals with northern European ancestry, especially Scandinavian, and in certain other populations, including some of the nomadic peoples of the middle east and Africa.
• Lactase non-persistence (lactose intolerance) is observed in a majority of the world's populations, including most of those with Asian or African forebearers.

Genetics of Lactase Persistence

Lactose persistence and non-persistence reflect inheritence of different alleles of the lactase gene. Lactase persistence, and therefore lactose tolerance, is inherited as a dominant trait. Lactose intolerance is the result of being homozygous for the recessive lactase allele that is poorly expressed after early childhood. Being homozygous or heterozygous for the persistence allele allows lactase expression after the time when lactase expression is normally down-regulated. In some circumstances, heterozygotes can manifest partial intolerance, indicating that this is an incompletely dominant gene.

There are a number of polymorphisms within the human lactase gene, and "persistence genes" appear to have arisen multiple times independently in human populations. Data from several studies indicate that in European populations, the difference between persistence and non-persistence results from the difference in a single nucleotide located 13,910 bases upstream of the transcriptional start site of the lactase gene. In virtually all cases examined, a T at this position is associated with lactose persistence, while a C is observed in the non-persistent allele. Interestingly, this polymorphism that appears to potently affect lactase gene expression is embedded in an intron of an adjacent gene. Different single nucleotide polymorphisms at roughly -14,000 bp relative to the transcription start site of the lactase have been implicated in lactase persistence within African populations. The mechanism by which these minor differences in DNA sequence affect lactase gene expression is not known.

The apparent convergent evolution of lactase persistence among human populations is best explained as an adaptive response to the shared selective pressure resulting from domestication of dairy animals and consumption of milk during adulthood. Indeed, sequencing of DNA from skeletal remains of eight neolithic individuals who lived across Europe between 5800 and 5000 years BC revealed that all were homozygous for the lactase non-persistence allele, lending support to the hypothesis that the lactose-persistence mutation was selected for following the domestication of dairy animals.

Clinical Signs and Diagnosis of Lactose Intolerance

Three forms of lactose intolerance are recognized:

1. Primary lactose intolerance: the is the common form of lactose intolerance in which lactase gene expression turns off in childhood, and the individual is relatively lactase deficient as a teenager and adult
2. Secondary lactose intolerance: a number of diseases affecting the small intestine (inflammatory conditions, viral infections) can result in temporary lactase deficiency in individuals that are normally lactose tolerant. In most cases, this deficiency resolves in a few weeks.
3. Congenital lactase deficiency: this is a very rare disorder in which lactase is deficient from birth

Clinical signs of lactose intolerance are triggered by consumption of more lactose than can be readily digested. There is substantial variability among intolerant individuals in the extent and severity of clinical response to ingesting even the same quantity of lactose.

Symptoms typically appear 30 minutes up to 1 to 2 hours following the lactose challenge, and include nausea, cramping, bloating, diarrhea, and flatulence. As described above, these signs reflect the osmotic effects of unassimilated lactose in the intestinal lumen, plus the fermentation products generated in the large intestine.

It is important to differentiate milk allergies from lactose intolerance. A number of milk proteins have been shown to induce allergic reactions that can be mistaken for lactose intolerance.

Lactose intolerance can be diagnosed and differentiated from other disorders in several ways:

• Lactose tolerance test: blood samples are collected at intervals following consumption of a lactose solution and assayed for glucose; individuals that are unable to digest lactose do not show an increase in blood glucose concentrations.
• Hydrogen breath test: if lactose is not digested in the small intestine, it passes into the large intestine and is fermented by microbes to a number of products, including hydrogen, which can be detected in breath; in normal circumstances, hydrogen is present in extremely low concentrations in exhaled breath.
• Genetic testing: simple tests are now available to determine the lactase polymorphism (described above) associated with intolerance.

Treatment and Management

There is no known cure for lactose intolerance, but this condition is easily managed by avoiding lactose or supplementing with lactase:

• Minimize consumption of lactose-rich dairy products, especially milk. Individuals vary quite a lot in how restrictive they have to be. Those that must severely restrict consumption of dairy products should likely take calcium supplements in another form.
• Consume reduced-lactose products. Lactose can be removed from milk and other dairy foods, and such products are widely available
• Consume a lactase supplement along with dairy products. A number of liquid or tablet preparations of lactase are available that assist digestion when consumed in conjunction with milk and other lactose sources.

There is no evidence for adaptive alteration of lactase expression. In other words, intolerant individuals cannot become tolerant by consuming small then increasing quantities of lactose.

References and Reviews

• Bodlaj G, Stocher M, Hufnagl P, etc: Genotyping of the lactase-phlorizin hydrolase -13910 polymorphism by LightCycler PCR and implications for the diagnosis of lactose intolerance. Clin Chem 2006; 52:148-151.
• Burger T, Kirchner M, Bramanti B, Haak W, Thomas MG. Absence of the lactase-persistence-associated allele in early neolithic Europeans. Proc Nat Acad Sci 2007; 104:3736-41.
• Crittenden RG, Bennett LE: Cow's milk allergy: a complex disorder. J Am Coll Nutr 24(6 Suppl):582S-91S, 2005.
• Evershed RP, Smith JD, Roffet-Salque M, Timpson A, Diekmann Y, et al. Dairying, diseases and the evolution of lactase persistence in Europe. Nature 2022; https://doi.org/10.1038/s41586-022-05010-7.
• Matthews SB, Waud JP, Roberts AG, Campbell AK: Systemic lactose intolerance: a new perspective on an old problem. Postgrad Med J 2005; 81:167-173.
• Montalto M, Curigliano V, Santoro L, etc: Management and treatment of lactose malabsorption. World J Gastroenterol 2006; 12:187-191.
• Ridefelt P, Hakansson LD: Lactose intolerance: lactose tolerance test versus genotyping. Scand J Gastroenterol. 2005; 40:822-826.
• Swallow DM: Genetics of lactase persistence and lactose intolerance. Annu Rev Genet 2003; 37:197-219.
• Tishkoff SA, Reed FA, Ranciaro A, etc: Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genet 2007; 39:31-40.

Updated July, 2022. Send comments to Richard.Bowen@colostate.edu