Review Article Lactose.docx

1、Review Article LactoseReview Article: Lactose Intolerance in Clinical Practice Myths and RealitiesM. C. E. Lomer, G. C. Parkes, J. D. SandersonAliment Pharmacol Ther. 2008;27(2):93-103. Background: Approximately 70% of the world population has hypolactasia, which often remains undiagnosed and has th

2、e potential to cause some morbidity. However, not everyone has lactose intolerance, as several nutritional and genetic factors influence tolerance.Aims: To review current clinical practice and identify published literature on the management of lactose intolerance.Methods: PubMed was searched using t

3、he terms lactose, lactase and diet to find original research and reviews. Relevant articles and clinical experience provided the basis for this review.Results: Lactose is found only in mammalian milk and is hydrolysed by lactase in the small intestine. The lactase gene has recently been identified.

4、Wild-type is characterized by lactase nonpersistence, often leading to lactose intolerance. Two genetic polymorphisms responsible for persistence have been identified, with their distribution concentrated in north Europeans. Symptoms of lactose intolerance include abdominal pain, bloating, flatulenc

5、e and diarrhoea. Diagnosis is most commonly by the lactose hydrogen breath test. However, most people with hypolactasia, if given appropriate advice, can tolerate some lactose-containing foods without symptoms.Conclusion: In clinical practice, some people with lactose intolerance can consume milk an

6、d dairy foods without developing symptoms, whereas others will need lactose restriction.Lactose intolerance is widespread throughout the world and subjects usually avoid milk and dairy products to improve symptoms. The disaccharide lactose is a unique carbohydrate present only in mammalian milk, 7.2

7、 g/100 mL in mature human milk, 4.7 g/100 mL in cows milk but is negligible in the milk of some marine mammals.1 For effective utilization, lactose requires hydrolysis by the enzyme lactase and, during infancy, provides an excellent source of energy at a time of rapid growth and development. An enha

8、nced understanding of lactase and its deficiency and why there is a special carbohydrate in milk is important for improved management of lactose intolerance.The enzyme lactase-phlorizin hydrolase, more commonly known as lactase, is a -galactosidase responsible for the hydrolysis of lactose to the mo

9、nosaccharides, glucose and galactose. These are absorbed by intestinal enterocytes into the bloodstream (Figure 1), glucose is ultimately utilized as a source of energy and galactose becomes a component of glycolipids and glycoproteins. The enzyme has two active sites, one hydrolysing lactose and th

10、e other phlorizin (an aryl -glucoside) and a range of dietary glycolipids.2 A number of actions of the phlorizin site are useful in humans and this explains why some enzyme activity is retained following the usual decline in enzyme expression after weaning from breast milk (see below).In lactase per

11、sistence, lactase-phlorizin hydrolase in the brush border efficiently hydrolyses lactose into galactose (Gal) and glucose (Glu) and is rapidly absorbed into the bloodstream taking luminal water with it. Hydrolysis typically occurs in the jejunum, which has low concentrations of bacteria 101-4 mL-1;

12、thus, little lactose is fermented.Lactase is present on the apical surface of enterocytes in the small intestinal brush border with the highest expression in the mid-jejunum. It is secured by its C-terminal end with most of the molecule protruding into the gastrointestinal lumen. The enzyme is produ

13、ced as a 220 kDa precursor peptide, which undergoes considerable post-transcriptional modification during transport to the cell surface as the mature 150 kDa protein. Luminal factors also contribute to final modification of the protein to produce the active enzyme by cleavage of two further amino ac

14、ids by pancreatic trypsin.3By week 8 of gestation, lactase activity can be detected at the mucosal surface in the human intestine. Activity increases until week 34 and by birth, lactase expression is at its peak. However, within the first few months of life, lactase activity starts to decrease (lact

15、ase nonpersistence). In most mammals, it declines at variable rates following weaning to undetectable levels as a consequence of the normal maturational down-regulation of lactase activity.4-6 In humans, approximately 30% of the population has continued lactase activity beyond weaning and into adult

16、hood (lactase persistence).7 This happens mainly in people of north European descent and relates geographically to the introduction of dairy farming approximately 10 000 years ago.8 Recent analysis of archaeological DNA suggests that genetic lactase persistence was rare in Northern Europeans prior t

17、o dairy farming. The so-called culture-historical hypothesis proposes that the high prevalence of lactase persistence in Northern Europeans occurred as a result of a more recent selection process enabling populations to rely on mammalian milk as an important component of the diet particularly at tim

18、e of poor harvest.9-11 An opposing hypothesis reverse cause proposed that dairy farming and milk consumption was adopted by those with pre-existing lactase persistence10,12,13 but evidence from archaeological DNA suggests that this is less likely.14Hypolactasia, or lactase deficiency, exists in thre

19、e distinct forms: congenital, primary and secondary. Congenital lactase deficiency is associated with the least lactase activity. It is a lifelong disorder characterized by failure to thrive and infantile diarrhoea from the first exposure to breast milk. Congenital lactase deficiency is extremely ra

20、re, with only around 40 cases having been reported. It is a single autosomal recessive disorder, but very little is known about the molecular basis.15 The only treatment is complete avoidance of lactose from birth. Lactase nonpersistence (primary lactase deficiency), as described above, occurs in th

21、e majority of humans. Secondary or acquired lactase deficiency refers to the loss of lactase activity in people with lactase persistence. It occurs as a result of gastrointestinal illness that damages the brush border of the small intestine, e.g. viral gastroenteritis, giardiasis or coeliac disease.

22、16,17 This is usually reversible.For effective utilization of lactose without symptoms of intolerance, only 50% of lactase activity is necessary15 and it is present only at the level that it is required, as is the case for other intestinal disaccharides.18For many years, it was thought that lactase

23、persistence in humans was the wild-type pattern.19 As the lactase nonpersistence phenotype is expressed in other mammals, this is now considered to be the ancestral type whilst lactase persistence is because of a mutation.The lactase gene is approximately 50 kb in size20 and located on chromosome 2.

24、21,22 Wild-type is characterized by lactase nonpersistence whilst two single nucleotide polymorphisms (SNPs) in the lactase gene have been associated with lactase persistence. These are C/T13 910 and G/A22 018 substitutions occurring 14 and 22 kb upstream of the 5-end of the lactase gene in a DNA re

25、gion, which functions as a cis-acting element influencing the lactase gene promoter.15,21,23 Studies suggest that C/T13 910 is the dominant polymorphism with the C allele linked to a decline in lactase mRNA expression. However, the exact mechanism of this decline after weaning is uncertain.24Individ

26、uals heterozygous for either SNP have intermediate lactase activity and are more susceptible to lactose intolerance at times of stress or gastrointestinal infection.5 This polymorphism does not provide a complete explanation as individuals with homozygous lactase persistence (genotypes TT and AA) ma

27、y occasionally develop lactose intolerance (i.e. acquired lactase deficiency.25 Adult homozygotes with nonpersistence (CC and GG) have virtually undetectable levels of intestinal lactase as a result of down-regulation of the brush border enzyme following weaning.26Hippocrates first described lactose

28、 intolerance around 400 years BC. but the clinical symptoms have become recognized only in the last 50 years.5 Up to 70% of the world population has lactase nonpersistence,5 but not all are intolerant to lactose as many nutritional and genetic factors influence tolerance.8,27Ethnic origin affects th

29、e frequency of lactose intolerance. In adults, white north Europeans, North Americans and Australasians have the lowest rates ranging from 5% in a British population to 17% in Finland and northern France. In South America, Africa and Asia, over 50% of the population has lactase nonpersistence and in

30、 some Asian countries this rate is almost 100%.1,4,15,23,28-36 Interestingly, in subjects from mixed ethnicity, a lower prevalence of lactase nonpersistence is observed where a high prevalence is detected in the native ethnic group.30The decline in lactase expression is usually complete during child

31、hood but the decline has also been reported to occur later in adolescence.33 The rate of loss of lactase activity also varies according to ethnicity but the physiological explanation for this difference in timing is currently unknown. Chinese and Japanese lose 80-90% of lactase activity within 3-4 y

32、ears after weaning, Jews and Asians lose 60-70% over several years postweaning and in white Northern Europeans it may take up to 18-20 years for lactase activity to reach its lowest expression.5Early studies of lactose digestion involved measuring blood glucose levels following a lactose load of 50 g, a significant increase in blood glucose after 30 min indicating high lactase activity.15,25 In research, serum measurements of 13C-labelled lactose following an oral dose have also been used, but are not appropriate for use in clinical practice.37More recently, lacta