Lactose Intolerance

Disaccharide lactose is the main carbohydrate in the milk. Lactose consists of monosaccharides galactose and glucose that can be taken up into the enterocytes and used as a source of energy only after hydrolysis in the intestinal tract by the enzyme lactase. Lactase activity is high during infancy, when milk is the main source of nutrition, and declines after the weaning phase in most mammals. This is also the case in the majority of humans up to 70% [8] throughout the world who are described as lactose intolerant (OMIM #223100).

Ethnic origin affects the frequency of lactose intolerance. In adults, white North Europeans, North Americans and Australians have the lowest rates of lactose intolerance, in South America, Africa and Asia, over 50% of the population has lactose intolerance and in some Asian countries this rate is almost 100% [8].

Lactose intolerance exists in three different forms: congenital, primary and secondary. Congenital lactase deficiency is a lifelong disorder and is associated with the lowest lactase activity. It is extremely rare single autosomal recessive disorder, but very little is known about its molecular basis [10]. Primary lactase deficiency occurs in the majority of humans and it is the form of lactose intolerance that can be genetically tested. Secondary or acquired lactase deficiency refers to the loss of lactase activity in people with lactase persistence. It could be caused by a gastrointestinal illness that damages the brush border of small intestine, e.g. viral gastroenteritis, giardiasis or celiac disease and is usually reversible [3].

The lactase gene (LCT) spans approximately 50 kb in the genome [1] and is located on chromosome 2 [5]. Lactose intolerance is a wild type phenotype, but the SNP (-13910 C/T) in the cis-acting element near the lactase gene have been associated with the lactose tolerance phenotype [10,2,9]. Adult -13910 CC  homozygotes have almost undetectable levels of intestinal lactase as a result of the down-regulation of the enzyme following weaning.

Among patients of European descent -13910 CC genotype was found to be almost completely associated with lactose intolerance [2]. Individuals heterozygous for the SNP have intermediate lactase activity and are more susceptible to lactose intolerance at times of stress and gastrointestinal infections [8]. Individuals with homozygous lactase persistence (genotype TT) may occasionally develop lactose intolerance, but in this case it is secondary [4].

Discovery of the SNP -13910 C/T that shows a complete association with lactose intolerance has lead to the genetic testing of adult-type lactose intolerance. The three genotypes of -13910 C/T perfectly correlate with the level of lactase activity in intestinal biopsy samples in several populations including Italians, Germans and Finns [2,7].

Genetic test of lactose intolerance may help to differentiate patients with primary hypolactasia from those with lactose intolerance caused by secondary hypolactasia. Also it is useful for differing lactose intolerance from irritable bowel syndrome which has very similar symptoms. So for the differentiation of adult-type hypolactasia from secondary causes of lactose intolerance, hydrogen breath testing (HBT) needs to be supported by genotyping [6]. In addition, unlike the HBT and LTT, the results of genotyping are not influenced by exogenous factors such as incomplete fasting, antibiotics or endoscopy before being tested. Genetic testing is also more comfortable for the patient and less time-consuming than traditional methods.

References:
[1]    W. Boll, P. Wagner, N. Mantei, Structure of the chromosomal gene and cDNAs coding for lactase-phlorizin hydrolase in humans with adult-type hypolactasia or persistence of lactase, American journal of human genetics 48 (1991) 889-902.
[2]    N.S. Enattah, T. Sahi, E. Savilahti, J.D. Terwilliger, L. Peltonen, I. Jarvela, Identification of a variant associated with adult-type hypolactasia, Nature genetics 30 (2002) 233-237.
[3]    E. Gudmand-Hoyer, H. Skovbjerg, Disaccharide digestion and maldigestion, Scandinavian journal of gastroenterology 216 (1996) 111-121.
[4]    M. Gugatschka, H. Dobnig, A. Fahrleitner-Pammer, P. Pietschmann, S. Kudlacek, A. Strele, B. Obermayer-Pietsch, Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males, Qjm 98 (2005) 857-863.
[5]    C.B. Harvey, M.F. Fox, P.A. Jeggo, N. Mantei, S. Povey, D.M. Swallow, Regional localization of the lactase-phlorizin hydrolase gene, LCT, to chromosome 2q21, Annals of human genetics 57 (1993) 179-185.
[6]    M. Kerber, C. Oberkanins, G. Kriegshauser, B. Kollerits, A. Dossenbach-Glaninger, D. Fuchs, M. Ledochowski, Hydrogen breath testing versus LCT genotyping for the diagnosis of lactose intolerance: a matter of age?, Clinica chimica acta; international journal of clinical chemistry 383 (2007) 91-96.
[7]    M. Kuokkanen, N.S. Enattah, A. Oksanen, E. Savilahti, A. Orpana, I. Jarvela, Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia, Gut 52 (2003) 647-652.
[8]    S.B. Matthews, J.P. Waud, A.G. Roberts, A.K. Campbell, Systemic lactose intolerance: a new perspective on an old problem, Postgraduate medical journal 81 (2005) 167-173.
[9]    L.C. Olds, E. Sibley, Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element, Human molecular genetics 12 (2003) 2333-2340.
[10]    D.M. Swallow, Genetics of lactase persistence and lactose intolerance, Annual review of genetics 37 (2003) 197-219.