lactose intolerance- symptoms, diagnosis and treatment

Lactose intolerance- symptoms, diagnosis and treatment

Nutrifocus1/2009

Nutrifocus • 1/20092

Dear reader,

Riitta Korpela, Ph.D.Vice President, Research, R&D, Valio Ltd

Professor, Institute of Biomedicine, University of Helsinki

Nutrifocus

Finnish researchers are pioneers in the study of lactose intolerance. Lacta-

se enzyme deficiency and its consequent symptoms were first described

in the 1960s. Typically far-sighted, Valio began to develop low lactose

products that would also suit lactose intolerants. The result was the HYLA®

product range in which lactose is degraded into glucose and galactose

using lactase in the manufacturing process. In 2001, Valio addressed

a clear consumer need in launching completely lactose free products

which have proven a great success in Finland, as well as Sweden,

Belgium, the Baltic States and Russia. The unique lactose free

manufacturing process has won international accolades and

received the Finnish Engineering Award.

The generality and genomics of lactase enzyme deficiency are quite well

known nowadays. While a DNA test now exists to identify the genome,

the genome in itself tells us nothing about an individual’s symptoms or

lack thereof, nor does it help in choosing the appropriate foods for daily

consumption. Health care professionals, however, have a wider range

of means at their disposal to help lactose intolerants. They are able to

suspect and diagnose it, and dietary solutions, lactose free dairy products,

can now be found on the market. Lactose intolerants need not eliminate

dairy products from their diet to lead a completely symptom-free life.

Bringing taste to life!

Editorial staff

Hanna HaponenNutritionist, M.Sc.Valio Ltd, R&DNutrition & Healthtel. +358 10 381 [email protected] Tuula TuureNutrition Manager, Ph.D.Valio Ltd, R&DNutrition & Healthtel. +358 10 381 [email protected] Published byValio Ltd, R&DPO Box 30, FI-00039 VALIOtel. +358 10 381 121fax +358 10 381 3019www.valio.fiwww.valio.com

Order fromValio Ltd, R&DNutrition & HealthPO Box 30, FI-00039 VALIOtel. +358 10 381 3030fax +358 10 381 3019 English translation byComword [email protected] LayoutHeidi Lithenius, Valio Ltd Printed in Finland byEdita Prima Oy, 2009 Cover photoRami Hanafi

Symptoms and diagnosis of lactose intolerance

The role of intestinal bacteria in lactose absorption

Contents

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Milk-related symptoms in children: lactose intole-rance or milk allergy?

The lactase enzyme generated in the epithelial cells of the small intestine degrades lactose. Diseases that damage the mucous membrane of the small intestine may temporarily decrease lactase enzyme production and thereby inhibit lactose degradation in the intestine. Common causes of secondary lactose intolerance include e.g. untreated celiac disease, infectious diarrhoea, and Crohn’s disease. Secondary lactose intolerance is temporary and will pass when the mucous membrane heals.

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Genetics of adult-type hypolactasia

What secondary lactose intolerance may indicate?

Lactase enzyme activity is normally high in all newborns. Hypolactasia and the symptoms of lactose intolerance caused by it develop at a different age in different populations. In small children, milk-related symptoms are most often caused by cow’s milk allergy, whereas in school children lactose intolerance symptoms become more common.

Dairy products are a source of many different nutrients. The beneficial health effects of calcium as observed in studies can be greater with calcium obtained from dairy products compared with that from calcium pills. This may be due to other minerals or protein in milk or the fact that nutrients are often obtained from dairy products in smaller doses than from pills, which may improve their utilisation. Page.............................................................................................................. 18

Treatment of lactose intolerance through diet

Milk – a challenge to multivitamin pills

Milk and dairy products are the principal source of lactose in the diet, but lactose is also used in the food industry. It is import-ant to lactose intolerant people that they are able to identify foods that contain lac-tose. If even small amounts of lactose cause symptoms, the diet has to be completely lactose free. A lactose free diet does not, however, mean a milk-free diet.

Stomach problems of various kinds are common in the western world. Lactose, the carbohydrate found in dairy products, may be one of the causes. The lactase enzyme is necessary for the absorption of lactose and if the enzyme is lacking then lactose, or at least most of it, is not degraded in the digestive tract. Non-degraded lactose may cause unpleasant intestinal symptoms which are known as lactose in-tolerance. Hypolactasia can be diagnosed e.g. with a lactose tolerance test. The latest method of diagnosis is a gene test.

Hypolactasia or primary lactose malab-sorption is the most common enzyme deficiency in humans and occurs in more than 70% of the world population. It is a recessively inherited trait i.e. its occurrence requires the inheritance from both parents of the gene associated with hypolactasia. In the course of human history, there have been gene mutations in some populations that keep lactase activity at a high level for the duration of a person’s life.

A number of studies have provided proof that the development of lactose intoler-ance symptoms is also affected by other factors besides the enzymatic degradation of lactose. Intestinal bacteria are known to contribute to the maintenance of the normal sensory and motor function of the digestive tract, and through fermen-tation the bacteria may also degrade carbohydrates, such as lactose. This may explain why some people with hypolac-tasia suffer no symptoms from lactose.

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Esophagus

Stomach

Small intestine

Large intestine

Lactose is a carbohydrate in milk

Lactose, or milk sugar, is the most important carbohydrate in milk. In chemical terms a disaccharide, it is composed of glucose and galactose (Figure 1). The milk of nearly all mammals contains lactose; however, the concentration varies by species. The lactose concentration in human milk is about 7%, whereas that of cow’s milk is about 5%.

Lactase is needed to digest lactose

Disaccharides are not as such absorbed from the gastrointestinal tract into the blood circulation until the bond between the two basic sugars is broken, a task performed by enzymes. The lactase enzyme on the small intestinal epithelium degrades lactose1. Re-leased from lactose, glucose and galactose are absorbed into the circulation via an active transportation mechanism. Compared with other dietary disaccharides, such as saccharose, lactose is degraded and absorbed very slowly2.

The body’s ability to degrade lactose depends on the amount and activity of the lactase enzyme present. The amount of the enzyme varies in different parts of the small intestine. The greatest amount of lactase activity is observed in the jejunal area in the middle section of the small intestine (Figure 2).

Small children have a good degree of lactase activity. It can even be measured in a foetus only a few months old. In some people, most or almost all of the intestinal lactase enzyme disappears when they grow up3,4. In fact, this happens to as much as 70% of the world’s population, and the phenomenon is termed pri-mary or genetic adult-type lactase deficiency. Secondary lactase deficiency may be caused by an external factor damaging the intestinal villi, and then lactase producing cells are temporarily

Symptoms and diagnosis of lactose intolerance

Katri Peuhkuri, Ph.D.Netnut – Nutrition information services

Figure 2. Lactase is formed in the small intestine. The intensity of the red colour illustrates the amount of lactase enzyme.

Figure 1. Lactose is composed of glucose and galactose joined together by a glycosidic bond.

destroyed, for example in connection with different acute and chronic intestinal diseases. When the factor causing the deficiency disappears and intestinal villi are healed, the lactase producing ability of epithelial cells is regained.

Unabsorbed lactose causes intestinal symptoms

The symptoms of lactose intolerance are caused by the fact that due to a deficiency of the lactase enzyme, lactose or at least most of it is not absorbed3. As a result of osmosis, unabsorbed lactose attracts water, and consequently, the water content of the intes-tine increases. If there is a large amount of unabsorbed lactose, intestinal volume increases thus accelerating small intestinal movements. As a result, chyme passes through the intestine more rapidly than usual. Consequently, the degradation and absorption of lactose is further hampered.

Water and unabsorbed lactose pass into the large intestine where part of bacteria feed on the lactose5. Acids and gases are produ-ced as a result of fermentation. The short chain fatty acids formed increase the acidity of the bowel contents, which accelerates colonic motility and may cause looser stools or diarrhoea. The gases formed, such as carbon dioxide, methane and hydrogen, stretch the intestines causing abdominal swelling and pain as well as flatulence, which are the most common symptoms of lactose intolerance (Figure 3). Intestinal movements may also slow and in these cases lactose intolerance causes constipation. The symptoms caused by lactose are temporary, and lactose is not known to cause permanent damage.

Nutrifocus • 1/2009 5

Figure 3. Picture A: Lactase degrades lactose. No symptoms of lactose intolerance. Picture B: Unabsorbed lactose in the large intestine causes lactose intolerance symptoms.

Table 1. Terms relating to lactose intolerance.

Lactose Milk sugar or milk carbohydrate. Lactase The digestive enzyme that degrades lactose molecules into glucose and galactose.

Hypolactasia Lactase enzyme deficiency. The opposite is normo- lactasia, which means reasonable or high lactase activity.

Lactose malabsorption A condition caused by hypolactasia with reduced degrading and absorption of lactose.

Lactose intolerance Disturbance in lactose absorption, with gastrointestinal symptoms typical to the condition.

The symptoms of lactose intolerance usually appear within a few hours of eating food that contains lactose. There are large indi-vidual differences in how the symptoms are experienced6. They may also vary from day to day, because not only the amount of lactose but also the meal as a whole and many physiological fac-tors such as intestinal acidity and bacterial strain may affect the way in which the symptoms are experienced. If removing lactose from the diet does not significantly reduce the symptoms, there may be other reasons involved, such as irritable bowel syndrome (IBS)7,8.

Lactase deficiency does not always cause intestinal symptoms typical to lactose intolerance. Most subjects suffering from lactase deficiency can drink a glass of milk (10–12 g of lactose) with a meal without presenting any symptoms9, whereas the most sensitive lactose intolerants experience disturbing symptoms even with smaller doses. People use the terms lactose intolerance and lactase deficiency as synonyms, although they in fact mean different things (Table 1).

Diagnosis by lactose tolerance test

Hypolactasia is usually diagnosed using a lactose tolerance test by which the glucose released after lactose intake or changes in

the gases in exhaled air are measured indirectly (Table 2)10. The patient drinks a dose of lactose, diluted into water, on an empty stomach after a night of fasting. The test solution usually contains 50 g lactose in 250–400 ml of water. In children, the amount of lactose is calculated according to the child’s weight at 1–2 g/kg. Blood glucose is measured after the test dose has been administered; in addition to the fasting value, blood glucose is measured 20, 40 and in many cases 60 minutes after consuming the test dose. Just a minor increase above the fasting value in blood glucose level suggests hypolactasia. Lactose has not been degraded and a corresponding amount of glucose has not been absorbed from the intestine into the circulation.

If the blood sugar level remains at 1.1–1.6 mmol/l, the result is uncertain, in which case the test can be repeated later or lactose intolerance DNA can be taken. The method of taking blood samples also confuses the results11. The reference limits for the interpretation of changes have been set on the basis of a capillary or fingertip blood sample. Nowadays, however, many laboratories draw blood samples from the veins, although venous and capillary glucose are only at an equivalent level in fasting samples. As blood glucose content increases, the capillary level is clearly higher. The limit of interpretation for lactose absorption in venous samples should clearly be lower than the currently used value of 1.1 mmol/l.

The lactose test is not suitable for everyone. For example, the test cannot be performed on diabetic patients, because the serum glucose level may change for other reasons. If glucose measurement is not possible or reliable, we can investigate whether or not there are any changes in galactose levels. Normally there is hardly any galactose in blood, because the liver rapidly converts it into glucose. In the tolerance test, the conversion of galactose into glucose is prevented by alcohol; the blood galactose level rises when lactose is degraded. The lactose test with ethanol is very seldom used nowadays.

Changes in the hydrogen and/or methane gas concentrations in exhaled air can be investigated after the intake of a lactose dose.


Table 2. Reference limits for lactose absorption measurement methods in clinical use. The methods in bold are the most com-monly used.

Measurement method Normal lactose tolerance Lowered lactose tolerance (malabsorption)

Blood glucose level increase ≥ 1,6 mmol/l increase ≤ 1,1 mmol/l

Blood galactose level increase ≥ 0,3 mmol/l increase < 0,3 mmol/l

Hydrogen breath increase < 20 ppm increase ≥ 20 ppm

Gene test C/T and T/T genotypes C/C genotype

The quantity of gases increases in exhaled air if the lactose in the test dose has not been degraded and has passed into the large intestine for use by microbes. A minimum increase of 20 ppm during follow-up is regarded as the diagnostic limit. Breath test is considered inconvenient because it requires a long follow-up period, whose length varies from one to three hours depending on the clinic.

The gases in exhaled air are affected by the composition of intes-tinal microbiota. Methane producing bacteria are predominant in about one fifth of persons with lowered lactose tolerance12. These bacteria use intestinal hydrogen, which causes only a minor increase in the hydrogen concentration of exhaled air. Similarly, antibiotic treatments preceding the study may tempor-arily affect the intestinal microbiota rendering the result of the hydrogen breath test unreliable.

None of these indirect test methods is completely reliable, although their sensitivity and accuracy are generally very good6. The most reliable results are obtained using two or more methods simultaneously6,13. Lactase activity can also be demon-strated directly in intestinal biopsy. However, this method is seldom appropriate unless there are other reasons for performing an intestinal biopsy.

As the newest method of diagnosis, genetic testing for lactase has become more general. The method employs DNA analysis to find lactase gene mutations. The sample is usually taken from blood or buccal mucous membrane. The method is quick, easy, and an extremely precise and cost-effective way to find lactase gene mutations4–16. As other factors such as celiac disease or intestinal infection may also have a secondary affect on lactose tolerance, intolerance cannot be totally excluded by C/T or T/T genotyping15.

A DNA test can be employed for adults and older school-children, but generally not for children under 10–12 years of age17. Gene divergence does not cause any symptoms in a small child, because lactase enzyme concentration does not fall until the age of 5–12 years. The C/T and T/T genotypes, however, are highly likely to exclude the lactose absorption disorder and its later development in all age groups.

All the above mentioned studies only measure lactase defi-ciency, not lactose intolerance per se. The development of possible symptoms caused by exposure to lactose is not taken

into account. In the diagnosis of lactose intolerance, sufficiently long-lasting and systematic follow-up of the symptoms de-veloped during the tolerance test is necessary to achieve the right diagnosis and treatment. The recommended duration of follow-up is at least three hours4,18.

Summary

• Lactose intolerance is a lactose absorption disorder with gastrointestinal symptoms such as abdominal pain, swelling and flatulence.

• The human body’s ability to degrade lactose depends on the amount and activity of the digestive enzyme lactase.

• Lactose absorption disorder is usually diagnosed using a lactose tolerance test in which lactose absorption is monitored by measuring the increase in blood glucose level. Gene tests are also generally used to study lactase gene mutations.

References

1. Zecca L, Mesonero JE, Stutz A et al. Intestinal lactase-phlorizin hydro lase (LPH): the two catalytic sites; the role of the pancreas in pro-LPH maturation. FEBS Lett 1998;435:225–8.2. Heitlinger LA, Li BU, Murray RD et al. Glucose flux from dietary disaccharides: all sugars are not absorbed at equal rates. Am J Physiol 1991;261:818–22.3. Lomer MC, Parkes GC, Sanderson JD. Lactose intolerance in clinical practice – myths and realities. Aliment Pharmacol Ther 2008;27:93–103.4. Matthews SB, Waud JP, Roberts AG et al. Systemic lactose intolerance: a new perspective on an old problem.Postgrad Med 2005;81:167–73.5. He T, Venema K, Priebe MG et al. The role of colonic metabolism in lactose intolerance. Eur J Clin Invest 2008;38:541–7.6. Peuhkuri K. Lactose, lactase, and bowel disorders. Reducing hypolac tasia-related gastrointestinal symptoms by improving the digestibility of lactose. Doctoral thesis. Helsinki University 2000.7. Vernia P, Ricciardi MR, Frandina C et al. Lactose malabsorption and irritable bowel syndrome. Effect of a long-term lactose-free diet. Ital J Gastroenterol 1995;27:117–21.8. Vesa TH, Seppo LM, Marteau PR et al. Role of irritable bowel syndrome in subjective lactose intolerance. Am J Clin Nutr 1998;67:710–5.9. Savaiano DA, Boushey CJ, McCabe GP. Lactose intolerance symptoms assessed by meta-analysis: a grain of truth that leads to exaggeration. J Nutr 2006;136:1107–13. 10. Peuhkuri K, Vapaatalo H, Korpela R. Wide variations in the testing of lactose tolerance: results of a questionnaire study in Finnish health care centres. Scand J Clin Lab Invest 2000;60:291–7.11. Irjala K. Laskimonäytteiden käyttö sotkee laktoosikokeen tulkintaa [in Finnish]. Suom Lääkäril 2007;62:2542.12. Vernia P, Camillo MD, Marinaro V et al. Effect of predominant met hanogenic flora on the outcome of lactose breath test in irritable bowel syndrome patients. Eur J Clin Nutr 2003;57:1116–9.13. Waud JP, Matthews SB, Campbell AK. Measurement of breath hydro gen and methane, together with lactase genotype, defines the current best practice for investigation of lactose sensitivity. Ann Clin Biochem 2008;45:50–8.14. Büning C, Genschel J, Jurga J et al. Introducing genetic testing for adult- type hypolactasia. Digestion 2005;71:245–50.15. Ridefelt P, Håkansson LD. Lactose intolerance: lactose tolerance test versus genotyping. Scand J Gastroenterol 2005;40:822–6.16. Piirainen A, Järvelä I, Malmi T. Laktoosin imeytymishäiriön diagnostis ten menetelmien kustannukset vertailussa [in Finnish]. Suom Lääkäril 2007;62:2081–4.17. Kerber M, Oberkanins C, Kriegshäuser G et al. Hydrogen breath testing versus LCT genotyping for the diagnosis of lactose intolerance: a mat ter of age? Clin Chim Acta 2007;383:91–6.18. Beyerlein L, Pohl D, Delco F et al. Correlation between symptoms developed after the oral ingestion of 50 g lactose and results of hydrogen breath testing for lactose intolerance. Aliment Pharmacol Ther 2008;27:659–65.


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Irma Järvelä, Associate ProfessorUniversity of Helsinki, Department of Medical Genetics

Genetics of adult-type hypolactasia

Figure 2. Incidence of hypolac-tasia (% of adult population) estimated on the basis of different studies3–6. The figures shown in the dark colour are from more reliable sources than those in grey.

Figure 1. Inheritance of the genetic variant linked to adult-type hypolactasia.

Low lactase activity is present in more than half of the world’s adult population (Figure 2). It is common in the populations of both Asia and Africa3. In the course of human history, there have been genetic variants in some populations that retain lactase activity at a high level throughout life. These variants have accumulated in Northern Europe, the Arabian Peninsula and in the small nomadic, pastoralist populations of Africa.

First described more than 40 years ago, adult-type hypolactasia or primary lactose malabsorption is the most common enzyme deficiency in humans1. Hypolactasia is a phenomenon linked to an infant’s normal development: lactase activity is high in neo-nates and infants for whom breast milk is an important source of nourishment. The decline in lactase activity after the age of five is linked to the evolution of man; weaning a child from breast milk makes it possible to produce new descendants.

Hypolactasia is a recessively inherited trait2. Recessive inherit-ance means that both parents are carriers of a genetic variant (i.e. they have the variant on one chromosome in a single form) and therefore tolerate lactose. If the child inherits the variant from both parents, i.e. gets double dose of the variant he/she will get adult-type hypolactasia trait (Figure 1). It is of notice, that one mutation is sufficient to keep lactase activity at a high level2.

a) Inheritance of adult-type hypolactasia. If one of the par-ents has the C/C

-13910 genotype (low lactase activity) and the

other the C/T-13910

genotype (high lactase activity), statis-tically half of their children inherit the C/C

-13910 genotype

and the other half the C/T-13910

genotype.

b) If both parents have the C/T-13910

genotype i.e. they are lactose tolerant, statistically every fourth child can inherit the hypolactasia genotype C/C

-13910. The other children would

have either the C/T-13910

or T/T-13910

genotypes. (If both parents have genotype T/T

-13910, all their children would also have

genotype T/T-13910

)


Summary

• Genetic variants of adult-type hypolactasia are inherited from both parents.

• Hypolactasia genotype C/C-13910

shows significant correlation with intestinal lactase activity after the age of 12.

• The decline in expression from the hypolactasia allele occurs simultaneously with the decline of lactase enzyme activity during childhood.

Genotype n Lactase activity (U/g protein; average) T/T

-13910 39 50,0

C/T-13910

86 29,9 C/C

-13910 17 6,5

Figure 3. Decline of lactase enzyme activity with age9.

Identification of the genetic variant associated with lactose tolerance

The lactase gene (LCT) coding lactase enzyme is located in the long arm 2q21–22 of chromosome 27. In studying the inherit-ance of genetic markers located close to the LCT gene, in large Finnish families whose lactose tolerance had been examined using lactose tolerance test (LTT), two single nucleotide variants could be identified, namely cytocine (C) to thymine (T) (C/T-13910) and guanine (G) to adenine (A) (G/A-22018), which were inherited in terms of hypolactasia and lactose tolerance. In the subsequent studies, only the C/T-13910 variant was inherited with lactase persistence/non-persistence with the C/C-13910 geno-type always associated with low lactase activity and C/T-13910 and T/T-13910 with high lactase activity. The variant is located at a distance of 13,910 base pairs from the lactase gene (LCT), in intron 13 of the minichromosome maintenance type 6 gene (MCM6)8. In the study on the decline of lactase activity com-prising 329 African and Finnish subjects under 20 years of age we observed that lactase activity began to decline among subjects with the C/C-13910 genotype after the age of 5 (Figure 3). The lactase activity in all subjects over 12 years of age with the geno-type C/C-13910 had declined to the adults’ level, less than 10 U/g protein (Table 1)10. Proportionally the same amount of lactase gene messenger RNA is produced in C-13910 and T-13910 alleles up to four years of age11. Messenger RNA production in the C-13910 allele begins to decrease thereafter. This phenomenon occurs simultaneously with the natural decline of lactase activity, which confirms the role of the C-13910 allele in lactase gene regulation. In adults, the T-13910 allele produces about 92% and C-13910 allele only 8% of lactase enzyme messenger RNA; in other words, T-13910 allele is responsible for the expression of the lactase gene at transcription level12.

Age (years)

Table 1. Lactase activity in the small intestine (low lactase level < 10 U/g protein) in different genotypes of lactase persistence/non-persistence in Finnish children and young adults (8–20 years of age).9

Genetic variants in lactose tolerance in Africa and the Arabian Peninsula

New genetic variants located near the C/T-13910 variant have been identified in African nomadic populations and in the Middle East. Of these, G/C-14010 has a statistically significant correlation

with lactase persistence as identified by lactose tolerance test, and is common in East Africa. In vitro studies have shown that this variant and the rare C/G-13907 and T/C-13913 variants enhance the expression of the lactase gene promoter13, 14. A founder mu-tation in the Arabian Peninsula, the T/G-13915 variant has shown a correlation with lactase activity in intestinal biopsy material15. These genetic variants located close to each other in the area of 100 base pairs support previous research results which show that the genetic variants associated with lactase persistence are located in the distal enhancer region.

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reReferences

1. Auricchio S, Rubino A, Landolt M et al. Isolated intestinal lactase deficiency in the adult. Lancet 1963;2:324–6.

2. Sahi T, Isokoski M, Jussila J et al. Recessive inheritance of adult-type lactose malabsorption. Lancet 1973;2:823–6.

3. Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol 1994;202:7S–20S.

4. Vesa T, Korpela R, Sahi T. Laktoosi-intoleranssi ja sen hoito [in Finnish]. Jyväskylä: Gummerus Kirjapaino Oy, 1993.

5. Almon R, Engfeldt P, Tysk C et al. Prevalence and trends in adult-type hypolactasia in different age cohorts in Central Sweden diagnosed by genotyping for the adult-type hypolactasia-linked LCT –13910C > T mutation. Scand J Gastroenterol 2007;42:165–70.

6. Borinskaya SA, Rebrikov DV, Nefedova VV et al. Molecular diagnosis and frequencies of primary hypolactasia in populations of Rus- sia and neighboring countries [in Russian]. Molekulyarnaya biologia 2006;40:1031–6.

7. Harvey CB, Fox MF, Jeggo PA et al. Regional localization of the lactase- phlorizin hydrolase gene, LCT, to chromosome 2q21. Ann Hum Genet 1993;57:179–85.

8. Enattah NS, Sahi T, Savilahti E et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002;30:233–7.

9. Kolho KL, Rasinperä H, Saarinen KM et al. Laktoosin imeytymishäiriön geenitestin soveltuvuus lasten ja nuorten tutkimiseen [in Finnish]. Suomen Lääkärilehti 2004;59:3627–9.

10. Rasinperä H, Savilahti E, Enattah N et al. Genetic test, which can be used to diagnose adult-type hypolactasia in children. Gut 2004;53:1571–6.

11. Rasinperä H, Kuokkanen M, Kolho K-L et al. Transcriptional downregula- tion of the lactase (LCT) gene during childhood. Gut 2005;54:1660–1.

12. Kuokkanen M, Enattah N, Oksanen A et al. Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. Gut 2003;52:647–52.

13. Ingram CJE, Elamin FF, Mulcare CA et al. A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence? Hum Genet 2007;120:779–88.

14. Tishkoff SA, Reed FA, Ranciaro A et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 2007;39:31–40.

15. Imtiaz F, Savilahti E, Sarnesto A et al. T/G-13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in Urban Saudi population. J Med Genet 2007;44:e89.


Katri Peuhkuri, Ph.D., Netnut – Nutrition information servicesTuula Tuure, Ph.D., R&D, Valio Ltd

The role of intestinal bacteria in lactose absorption

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Lactose intolerance has its origin in the small intestine. The symptoms, however, are primarily caused by the way in which unabsorbed lactose is processed by the bacteria in the large in-testine. This may provide an explanation as to why some people with diagnosed genetic lactose malabsorption do not suffer from symptoms caused by lactose.

1.5 kg of intestinal bacteria

The intestinal flora is essential to humans; it is known to partici-pate at least in the processing of nutrients and possibly medical substances, as well as in the development of the intestinal epithe-lium and immune system1.

In humans, there is a large amount of intestinal bacteria in the distal part of the small intestine and especially in the large intes-tine. Most of the intestinal bacteria belong to the main divisions Bacteroidetes and Firmicutes2. The former group mainly con-tains Bacteroides species and the latter Clostridium and Bacillus species. More than 80% of the intestinal bacteria species belong to these two groups. However, the spectrum of their effects as a whole is extremely broad and individualised, because separate strains of even the same species of bacteria may possess prop-erties different from each other.

Our knowledge of the intestinal microbiota is still incomplete. A considerable proportion of the known intestinal bacteria have only been detected with the aid of the new research methods, and there is hardly any information about their function. Most species of intestinal bacteria do not tolerate oxygen, and cannot be cultivated in laboratory conditions. Molecular biology methods are becoming more and more generally used in the studies of the 16S ribosomal RNA coding genes in particular. By studying the incidence and quantities of these genes in a bacterial population we can obtain information about the incidence and quantities of similar bacteria in the bacterial population concerned.

Studies have shown that there are considerable differences in intestinal microbiota between different persons, whereas the microbiota of a single individual appears to be highly stabile. Short-course dietary changes or antibiotics cause changes in the bacterial species. However, as the period of change ends, the species return to their original composition3. The stability of the microbiota can be explained by metabolic factors of the epithe-lial cells, receptor structures determined by the genotype and the specific adherence properties of bacteria related thereto.

Signs of the significance of intestinal bacteriain lactose intolerance

Carbohydrates, such as lactose, can be fermented (or decom-posed through fermentation) by intestinal bacteria. The bacteria obtain most of the carbohydrates from food; however, part of them originate in the body, such as detached epithelial cells, intestinal mucus and enzymes.

Many studies have shown that the development of lactose intolerance symptoms is affected by factors other than the degrading of lactose in the small intestine. Even if no increase of lactase enzyme activity in the epithelial cells of the small intestine has been observed in clinical studies after it decreased from the levels of early childhood4, a long-term use of products containing lactose can reduce intestinal symptoms and the amount of hydrogen exhaled with tidal air5. The gastrointestinal tract has theability to adapt. This is believed to be linked to intestinal microbiota, because e.g. antibiotic treatment may temporarily change – either increase or decrease – the symptoms


Figure 1. Lactose is through various intermediate phases fer-mented by intestinal microbiota into short chain fatty acids and gases7.

caused by lactose6. These results indicate that the symptoms of lactose intolerance are affected by enzymatic degradation and absorption of lactose in the small intestine and also by the ability of intestinal bacteria to handle lactose.

b-galactosidase of bacteria also degrades lactose

The lactase contained in the intestinal microbiota, b-galactosi-dase, can degrade lactose obtained from food into glucose and galactose in the same way as does the enzyme contained in epithelial cells7. Released glucose and galactose may be absorbed for use by epithelial cells or into the blood circulation, and can also be utilised by other intestinal microbes.

The degree of lactose degradation does not clearly explain the symptoms. Persons with lactose maldigestion experience the symptoms differently, even where the degree of lactose degrad-ation was the same8. In experimental study models, no significant differences are observed either in the b-galactosidase activity of intestinal bacteria of different individuals or in the effectiveness of lactose degradation by bacteria9,10.

Consequently, the ability of microbes to degrade lactose in the large intestine does not seem to explain the differences observed in how the symptoms are experienced. Moreover, it must be noted that the lactase enzyme function of intestinal bacteria is most active close to neutral acidity (pH 6–8), which is predominant in the small intestine. The lactase activity of bacteria decreases and lactose remains unfermented in the more acidic conditions in the large intestine. The level of acidity in the large intestine varies, which is one factor that can explain the large degree of difference in lactose tolerance between different individuals.

Does the removal of metabolites have a decisive significance?

The product formed from lactose in the large intestine and its removal seems to be crucial to the way in which the symptoms are experienced. Part of the glucose and galactose released in the large intestine is absorbed relatively quickly, but it is not knownhow much remains for use by microbes and what affects the quantity concerned. This may be one important factor that explains the differences between individuals in experiencing symptoms.

The species and proportions of intestinal microbiota may affect further processing of glucose and galactose and the metabolites from the different stages of the process. Short chain fatty acids (acetate, propionate and butyrate), as well as gases such as hydro-gen, carbon dioxide and methane, are formed from glucose and galactose via various intermediate phases (Figure 1)7. Short chain fatty acids are absorbed in the large intestine, the mucous mem-brane cells of the large intestine utilise them (butyrate in particular), and they accumulate into bacterial mass or are excreted in faeces. The gases formed can be further utilised by bacteria, they are also absorbed into the blood circulation, and are evacuated through the lungs in tidal air and through the rectum as intestinal gases.

Usually, short chain fatty acids are quickly and effectively absorbed in the large intestine7. However, the intestinal microbiota of hypolactasic humans seem to produce lactate, acetate, propionate and butyrate from lactose, glucose and galactose, more so and faster than the bacteria of people with normal lactose absorption10.

The effectiveness of absorption varies in different parts of the large intestine. Acetate is best absorbed at the beginning of the large intestine and butyrate at the end of it, whereas propio-nate is absorbed effectively throughout the large intestine. If the formation of these short chain fatty acids exceeds the ability of the intestine to evacuate them, they start to accumulate in the intestines. The intermediate products such as lactate, ethanol and succinate usually disappear quickly, but they may also accu-mulate in the intestines if large amounts of them are released.

There are also individual differences in the formation and elimi-nation of gases released in fermentation. In theory, 17 litres of hydrogen are formed as a result of the colonic fermentation of 50 g of lactose (the usual dose in the lactose tolerance test cor-responds to the lactose dose in one litre of milk)7. If this large amount of gas remained in the large intestine, it would stretch the intestine and cause severe symptoms. The main part of the gases released in fermentation is, however, evacuated through other bacterial reactions.

Aside from the variation of species of intestinal microbiota, their concentrations in different parts of the intestines can affect the bacterial fermentation of unabsorbed carbohydrates, the elimination of released metabolites from the intestines, and the development of lactose intolerance symptoms. In a state of balance, the formation and removal of the end and intermediate products of fermentation reactions is regular and effortless. This is affected both by the intestinal microbiota as a whole and its metabolic activity, but particularly by the ability of the large intestine to evacuate the intermediate and end products formed.

Visceral sensitivity

The ability of the intestines to transport gas and evacuate it either through tidal air or as intestinal gases is usually very good.


Summary

• The onset of lactose intolerance symptoms is affected by the way in which the large intestinal microbiota handles unabsorbed lactose.

• There are differences between humans especially in how effectively the intermediate and end products of lactose fermentation are evacuated from the large intestine. • The symptoms can be explained by differences in the sensitivity to intestinal pain.

• The use of probiotics in modifying the intestinal microbiota has not been observed to have a significant effect on lactose-induced symptoms in short-term studies.

Probiotics are live cultures of one or more bacterial strains obtained in food or pharmaceutical preparations; their purpose is to improve the composition of microbial strains in the gastro-intestinal tract and have a beneficial effect on the host. Certain probiotic lactobacilli have lactase activity, but there are consid-erable differences between different probiotics18.

Research results concerning the benefits of probiotics in lactose intolerance are controversial. In a comparison of the results of ten studies, probiotics were not observed to have any clear effects in terms of decreasing the symptoms, even though some people found that they helped18. The comparative study exam-ined the efficacy of one dose of probiotics on the symptoms caused by one test dose of lactose. Using probiotics for a longer period of time can in theory be more effective, as has been suggested by a study in which bifidobacteria added to yoghurt affected the intestinal microbiota; during a two-week pilot study they increased b-galactosidase activity measured in faeces and decreased the symptoms caused by lactose19.

Conclusion

The lactase enzyme present in the epithelial cells of the small intestine, and the activity of the enzyme, naturally play a sig-nificant role in lactose absorption. If lactose is not degraded in the small intestine, it is not absorbed, either. The amount of the lactose, speed of gastric emptying, and intestinal transit time, also play a central role in the ability of the lactase enzyme to degrade the lactose dose in food. As far as the onset of symp-toms is concerned, the function of intestinal microbiota, as well as their quantity and quality, and particularly the ability of the large intestine to process the intermediate and end products of lactose degradation, are decisively significant. An appropriate microbiota utilises the unabsorbed lactose entering the large intestine effectively, which cannot perhaps be achieved by a different kind of microbiota.

It remains to be seen whether intestinal symptoms caused by unabsorbed carbohydrates can be precisely treated by processing the intestinal microbiota.

If one of these routes is ineffective, gases accumulate in the intestine and stretch it. Studies have not, however, shown sig-nificant differences in the formation of gas or its removal from the body, when making comparisons between those who suffer from lactose malabsorption and those who do not11,12.

Lactose intolerant individuals with severe symptoms may be more sensitive to pain in the intestinal area. Differences have previously been observed in intestinal symptoms caused by unabsorbed carbohydrates such as fructo-oligosaccharides13. Di Stefano’s research group observed that the pain caused by unab-sorbed lactulose, the test carbohydrate, was sensed more clearly and severely by lactose intolerant than symptom-free personswith diagnosed hypolactasia or persons who did not have hypo-lactasia14. No differences were observed between the groups in gastric emptying, intestinal transit time or gas formation.

These studies show that the symptoms of lactose malabsorp-tion may be experienced differently, depending on how gas and stretching in the intestines is sensed.

The lactase in sour milk products

Sour milk products, such as yoghurts and matured cheeses, suit many lactose intolerant consumers better than do other dairy products, as has been observed in many clinical studies15.Better tolerance is based on the use of lactic acid bacteria, with lactase activity, in the production of these products. Lactic acid bacteria such as members of the Lactobacillus family degrade lactose both during the manufacture of the product and pos-sibly also in the gastrointestinal tract. With regard to degradation in the gastrointestinal tract, it is crucial how well the bacterial structures can protect the lactase activity of the bacterium i.a. from gastric acidity and bile acids. It has been estimated that lactobacilli could reduce the amount of lactose in the product by as much as a half, partly prior to consumption during the fermentation process during manufacture, and partly in the gastrointestinal tract16. However, controversy exists in the re-search results with regard to the persistence of lactase activity in the gastrointestinal tract17.

The higher osmolarity and energy content of sour milk products compared with milk slow the gastric emptying and intestinal transit time, which also enhance the potential of the intestinal lactase enzyme to degrade more slowly the lactose entering the intestine15. Continuous consumption of sour milk products may change e.g. intestinal acidity, the composition of the intestinal microbiota, or lactose fermentation, so that it reduces the inci-dence of symptoms or of experiencing them.

Could the symptoms be alleviated by treatingintestinal microbiota with probiotics?

Because the balance between the formation and removal of the osmotically active compounds resulting from lactose fermen-tation has a crucial effect on the symptoms, some trials have been directed at influencing the amount of intestinal microbiota and their metabolic activity by modifying the microbiota with probiotics.


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References

1. Guarner F, Malagelada J-R. Gut flora in health and disease. Lancet 2003;360:512–9.

2. Eckburg PB, Bik EM, Bernstein CN et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635–8.

3. DeLa Cochetiere MF, Durand T, Lepage P et al. Resilience of the do- minant human fecal microbiota short-course antibiotic challenge. J Clin Microbiol 2005;43:5588–92.

4. Swallow DM. Genetics of lactase persistence and lactose intolerance. Annu Rev Genet 2003;37:197–219.

5. Hertzler SR, Savaiano DA. Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. Am J Clin Nutr 1996;64:232–6.

6. Chassany O, Michaux A, Bergmann JF. Drug-induced diarrhoea. Drug Saf 2000;22:53–72.

7. He T, Venema K, Priebe MG et al. The role of colonic metabolism in lactose intolerance. Eur J Clin Invest 2008;38:541–7.

8. Vonk RJ, Priebe MG, Koetse HA et al. Lactose intolerance: analysis of underlying factors. Eur J Clin Invest 2003;33:70–5.

9. He T, Priebe MG, Vonk RJ et al. Identification of bacteria with beta- galactosidase activity in faeces from lactase non-persistent subjects. FEMS Microbiol Ecol 2005;54:463–9.

10. He T, Priebe MG, Harmsen HJ et al. Colonic fermentation may play a role in lactose intolerance in humans. J Nutr 2006;136:58–63.

11. Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med 1975;293:524–6.

12. Hammer HF, Petritsch W, Pristautz H et al. Evaluation of the patho- genesis of flatulence and abdominal cramps in patients with lactose malabsorption. Wien Klin Wochenschr 1996;108:175–9.

13. Teuri U, Vapaatalo H, Korpela R. Fructooligosaccharides and lactulose cause more symptoms in lactose maldigesters and subjects with pseudohypolactasia than in control lactose digesters. Am J Clin Nutr 1999;69:973–9.

14. Di Stefano M, Miceli E, Mazzocchi S et al. Visceral hypersensitivity and intolerance symptoms in lactose malabsorption. Neurogastroenterol Motil 2007;19:887–95.

15. de Vrese M, Stegelmann A, Richter B et al. Probiotics – compensation for lactase insufficiency. Am J Clin Nutr 2001;73:421S-9S.

16. McDonough FE, Hitchins AD, Wong NP et al. Modification of sweet acidophilus milk to improve utilization by lactose-intolerant persons. Am J Clin Nutr 1987;45:570–4.

17. Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr 2004;80:245–56.

18. Levri KM, Ketvertis K, Deramo M et al. Do probiotics reduce adult lactose intolerance? A systematic review. Fam Pract 2005;54:613–20.

19. He T, Priebe MG, Zhong Y et al. Effects of yogurt and bifidobacteria supplementation on the colonic microbiota in lactose-intolerant subjects. J Appl Microbiol 2008;104:595–604.


Milk-related symptoms in children: lactose intolerance

or milk allergy? Laura Piirainen, Ph.D. (Food Science), B.M.National Institute for Health and Welfare

Table 1. Classification and symptoms of lactose intolerance and cow’s milk allergy. In early childhood, the symptoms are most often caused by milk allergy, at school age and adulthood by lactose intolerance.

Symptoms appear in the infant immediately after milk feeding has begun and continue throughout life

A rare inherited disease

Symptom is severe diarrhoea

Affects mainly adults and school-age children

Inherited decrease in lactase enzyme activity to approximately 10% after early childhood

Symptoms are intestinal pain, rumbling, and flatulence

In children, undiagnosed celiac disease and rotavirus diarrhoea are the most common causes of secondary lactose intolerance Lactose tolerance normalises once the intestines heal after the disease has been treated

Defence mechanisms reacting towards milk proteins

Most common in infants, often heals by school age

Blood contains a great deal of IgE antibodies to milk and high overall IgE

Intestinal, skin, and general symptoms

Immediate cow’s milk allergy

Cow’s milk allergy

Secondary lactose intolerance

Primary lactose intolerance

Congenital lactose intolerance

Lactose intolerance Symptoms caused by lactose malabsorption

Delayed cow’s milk allergy Affects mainly infants and school-age children

Non-IgE mediated

A delayed form of milk allergy in school-age children with intestinal inflammation, increase in lymphoid tissue, and activated defence mechanisms

Most often with intestinal symptoms

Lactose intolerance is rare in preschool age children. In small children, the cause of milk-related symptoms is most often an allergy to proteins in cow’s milk, whereas in adults it’s usually lactose intolerance.

Lactose intolerance is rare in small children

A complete absence of the lactase enzyme at birth (congenitallactase deficiency, CLD) is a rare, hereditary disease in the Finnish disease heritage1. The symptom is severe osmotic diar-rhoea immediately after the child starts on milk for the first time. Statistically speaking, less than one child per year is born with this disease in Finland. Normally the bacteria in the colon employ lactose as a source of energy, releasing gases i.e. carbon-dioxide and hydrogen. The intestinal microbiota is undeveloped in infants, so congenital lactase deficiency causes severe watery diarrhoea. The bacterial strain in the colon develops into similar bacteria as in adults once the child starts eating ordinary food.

The complete absence of lactase is considerably rarer than pri-mary lactase deficiency, which refers to a genetically inherited decrease in lactase activity after early childhood. Research on lactose tolerance in preschool and school age children is challenging2. As much as 30% of the results achieved through traditional lactose tolerance tests may be incorrect. Genetic tests are poorly suited to children – the test reveals whether the child has an inherited tendency towards a decrease in lactase activity but not whether the decrease has already started (see article Symptoms and diagnosis of lactose intolerance in this publication). Lactose intolerance in children is most often detected by a simple elimination/challenge test.

Milk-related symptoms in infants

According to extensive epidemiologic studies, approximately 2% of infants are allergic to cow’s milk. The allergy is characterised by symptoms in the gastrointestinal tract and by skin symptoms. The symptoms may be immediate i.e. IgE mediated, or delayed i.e. non-IgE mediated. Nearly all children outgrow milk allergy by the age of 3–7.

An allergy to cow’s milk in early childhood can usually be distin-guished easily from lactose intolerance based on the symptoms (Table 1). However, if the child’s symptoms (loose stools, bloated stomach and pains) indicate lactose malabsorption, the cause may also be a secondary lactase deficiency (see article What secon-dary lactose intolerance may indicate? in this publication).


Summary

• In small children, the most common reason for milk-related symptoms is an allergy to cow’s milk.

• Cow’s milk allergy is rare in school-age children and adults. In school-age children, the allergy mainly occurs in delayed form.

• Lactose malabsorption develops at different ages in different populations, in Finnish children mainly at school age.

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Milk-related symptoms in school-age children

Symptoms caused by lactose intolerance become more common at school age. The frequency of lactose malabsorption varies greatly between nations, and the decrease in lactase enzyme activity occurs at different ages in different populations. In almost all Asians and Africans, lactase activity has already fallen by the age of two. In Finnish children, lactose malabsorption develops mainly at school age and affects approximately 5% of 7 year-olds and 15% of 15 year-olds. Despite the decrease in the lactase enzyme, most people are able to consume reasonable amounts of milk, especially sour milk products, without deve-loping symptoms. Today, it is considered unnecessary to avoid lactose unless it does in fact cause symptoms. However, children who have inherited primary lactase deficiency seem automat-ically to decrease their milk consumption3.

Milk allergy is rare in school-age children and adults. If lactose intolerance does not explain the stomach symptoms caused by milk, the symptoms may be caused by milk allergy. Some children have IgE mediated allergy symptoms until they reach school age. The symptoms are mainly manifest on the skin, similar to those of immediate milk allergy in infancy, and can thus easily be distinguished from lactose intolerance. Most of these children have had the allergy since early childhood and often have other allergic diseases as well, e.g. allergic rhinitis, asthma, and atopic dermatitis.

It has been proposed that as many as half of the children who have been allergic to cow’s milk in early childhood suffer from milk sensitivity with intestinal symptoms from large amounts of milk at school age, even if they have tolerated milk since the allergy in early childhood4. Immediate IgE mediated symptoms have disappeared but the delayed intestinal symptoms have de-veloped afterwards. Milk seems to be the single most significant food ingredient to cause symptoms, but symptoms caused by cereals have also been detected.

No cell changes, typical to an allergy to cow’s milk in early childhood, can be detected on the intestinal mucous mem-brane of these school-age children suffering intestinal symp-toms; instead, an increase in intestinal lymphoid tissue, minor inflammations, and a slight activation of defence mechanisms is typical. Similar findings arise, whose implications are often more severe, for other immunologic diseases as well e.g. celiac disease, type 1 diabetes, rheumatoid arthritis and Crohn’s disease. Little is known about the phenomenon of delayed milk allergy.

References

1. Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency. A clinical study on 16 patients. Arch Dis Child 1983;58:246–52.

2. Kolho K-L, Rasinperä H, Järvelä I et al. Laktoosin imeytymishäiriön geenitestin soveltuvuus lasten ja nuorten tutkimiseen [in Finnish]. Suom Lääkäril 2004;39:3627–9.

3. Rasinperä H, Savilahti E, Enattah NS et al. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004;53:1571–6.

4. Tikkanen S, Kokkonen J, Juntti H et al. Status of children with cow’s milk allergy in infancy by 10 years of age. Acta Paediatr 2000;89:1174–80.


What secondary lactose intolerance may indicate?

Erkki Savilahti, ProfessorHUS (Helsinki and Uusimaa Hospital District), Hospital for Children and Young People

Jutta

Kuu

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A precondition for the absorption of lactose in milk is its en-zymatic degradation, which occurs with the help of the lactase enzyme of the epithelial cells of the small intestine. A large number of diseases focusing on the small intestine may cause deficiency of lactase expression on the intestinal mucous mem-brane. The same diseases also show lowered levels of other en-zymes that degrade disaccharides. When the concentrations of enzymes degrading intestinal disaccha-rides in these diseases are studied, the proportions of lactase/saccharase enzymes that degrade disaccharides are within normal limits (over 0.2), although the lactase level can be very low. Then again, a simultaneous decrease in other disaccharidases does not usually cause any symptoms.

The most common cause of secondary lac-tase deficiency is the acceleration of epith-elial cell destruction in the small intestine to such an extent that the crypt cells are unable to compensate for it. As a result, the quantity of mature epithelial cells decreases and villi become shorter. Secondary lactase deficiency is due to a decrease in the number of epithelial cells and the fact that the cells are not mature for sufficient synthetisation of lactase enzyme.

This situation is most typical in untreated celiac disease. The villi at the beginning of the small intestine have disappeared and biopsies taken in the area show low lactase enzyme levels in 70% of adult patients. As lactose tolerance is most decisively affected by the lactase activity of the whole small intestine, lactose does not, however, cause symptoms in such a large proportion of patients suffering from celiac disease. The disease has caused damage at the beginning of the small intestine, while various lengths of more distal parts of the intestine can be quite normal. Today, the predominant symptom of celiac disease in children is abdominal pain which often results from secondary lactase deficiency and has a con-nection with drinking milk.

When celiac disease involving abdominal symptoms is diagnosed, the patient should

reduce their lactose intake until the epithelial cells of the small intestine have healed, which usually takes no more than 6 months. Products made through splitting lactose (HYLA®) or those from which lactose has been completely removed are suit-able for these patients. Lactose restriction should not be continued unnecessarily. It is possible that the patient suffers from concomitant, primary lactase deficiency, which can be


checked, for example, using a gene test. However, celiac disease and primary lactase deficiency are in no way connected with each other.

The connection between milk allergy with intestinal symptoms and secondary lactase deficiency has caused a lot of confusion. A very similar degeneration of epithelial cells and villus atrophy to what we see in untreated celiac disease are linked to severe milk allergy involving intestinal damage, which was formerly termed intolerance. Diseased babies acquired symptoms from both milk protein and lactose, and it was at first necessary to elim-inate both from the diet. In milk allergy, too, lactose tolerance was normalised through the healing of epithelial cells during the elimination diet, in other words it was a case of secondary lactase deficiency. Almost all such cases have disappeared in the last few decades. In recent years, most patients suffering secondary lactase deficiency have experienced severe diarrhoeic symptoms soon after birth. The clinical picture resembles that of congenital lactase deficiency, but also requires the elimination of milk protein. In some patients, sensitivity to milk protein has been demonstrated later, while in others it has been cured and milk protein no longer caused symptoms to the infant at the age of one, and no lactase deficiency was observed. The primary disease could have been severe neonatal intestinal infection.

Secondary lactase deficiency also results from intestinal infec-tions of the small intestine. Rotavirus causes epithelial damage and a temporary decrease in lactase activity. In most cases, the remaining activity in the intestine is quite sufficient to split lactose, and consequently, instructions to restrict lactose intake have not generally been given in connection with infectious diarrhoea. If, after the sudden onset of diarrhoea, the diar-rhoea and abdominal symptoms persist for longer than a week, restriction of lactose intake may reduce the symptoms. In these cases it is always a temporary phenomenon, and the diet can be normalised after the symptoms have disappeared. Causes of secondary lactase deficiency, which is rare in Finland, include parasitic infections, such as giardiasis, which damage epithelial cells.

Lactase enzyme activity can also be secondarily reduced by an increased amount of intestinal microbiota; the bacteria may cause detachment of the enzyme from the epithelial cells. In-creased bacterial fermentation is typical of intestinal diseases that involve an obstacle, as in some patients suffering from Crohn’s disease, where inflammation of the small intestine can also decrease the amount of lactase enzyme; whereas lactase de-ficiency is not associated with ulcerative colitis, although some patients have symptoms following lactose intake, probably due to greater sensitivity of the large intestine to stretching caused by gases. This may result from abundant lactose intake, particularly if the patient suffers from maturity-onset primary lactase deficiency. In all the above mentioned cases, malnutrition worsens second-ary lactase deficiency and can be the sole cause of the condition in very young babies. Secondary lactase deficiency can be an additional factor that worsens the symptoms of many intes-tinal diseases; temporary restriction of lactose intake in the diet is required in these cases. Restriction should not be employed if there is some other solution, or nutritionally valuable dairy products are eliminated in vain.

Summary

• Diseases focusing on the small intestine mucous membrane can temporarily reduce lactase enzyme production and thereby hamper degradation of lactose in the intestine.

• Common causes of secondary lactose intolerance include e.g. untreated celiac disease, infectious diarrhoea and Crohn’s disease.

• Once the factor causing secondary lactose intolerance is eliminated and the intestinal villi recover, the epithelial cells regain their ability to produce lactase.


Milk – a challenge to multivitamin pills

Hanna Haponen, M.Sc., Nutritionist, R&D, Valio Ltd

Figure 2. Vitamin and mineral intake from three glasses (6 dl) of milk compared to dietary recommendations for adults6. Vitamin D intake has been calculated from milk with added vitamin D (0.5 µg/100 g).


Water 87–91%

Carbohydrate 4.8 %, of which 100% lactose

Protein 3.3%, of which 80% casein 20% whey protein

Fat 0–4.4%, of which 55% saturated fatty acids 20% monounsaturated fatty acids 2.5% polyunsaturated fatty acids 0.5% conjugated linoleic acid (CLA) 2.5% other trans fatty acids 8% other fatty acids 12% glycerol

Fat soluble and water soluble vitamins e.g. B12

and B2, niacin

Minerals e.g. calcium, phosphorus, iodine, selenium, zinc, potassium

Figure 1. Nutritional value of milk.

MiehetNaiset

foolihappo

tiamiini

magnesium

kalium

niasiini

sinkki

seleeni

D-vitamiini

jodi

B2-vitamiini

kalsium

fosfori

B12-vitamiini

0 20 40 60 80 100 120 140

% päivän saantisuosituksesta

Dairy product consumption has been associated in various studies with a healthy diet and abundant nutrient intake1–4. The versatile composition of milk and dairy products makes them an important source of many minerals and vitamins (Figure 1). As a natural source of calcium milk is irreplaceable – in the Finnish diet, over 70% of the calcium comes from milk and dairy products5.

The recommended calcium intake for adults is 800 mg/day6. This can be satisfied with 6 dl of liquid dairy products and 2–3 slices of cheese. Milk contains many other important nutrients besides calcium. It is a source of phosphorus, iodine, vitamins B12 and B2, thiamine, niacin, vitamin B6, folic acid, zinc, potassium, and magnesium (Figure 2). The body uses these nutrients for e.g. metabolism, nervous system functions, energy production, and the building and maintenance of teeth and bones. With the exception of organic products, liquid dairy products produced in Finland contain added vitamin D and are thus a good source of the vitamin. Dairy products also contain lots of high quality protein.

The amount of fat and lactose present in milk depends on the selection of the most suitable type of milk for own consumption. Low lactose Valio HYLA® milk contains less than 1% lactose, whereas Valio Zero LactoseTM milk drink contains no lactose whatsoever. The fat content in milk varies from 0–3.5%.

Milk and bones

Dairy products contain several nutrients that are important for bone health. Intervention trials conducted as long ago as the 1920s showed that the growth of children who consumed milk daily at school was approximately 20% greater than that of the children in the control group7,8. More recent intervention trials have confirmed the importance of dairy consumption for adoles-cents in particular; high milk consumption has an effect on peak bone mass9–13 and reduces the risk of osteoporosis in later life. Low bone mineral density is the main cause underlying osteo-porotic fractures and one which can be countered by sufficient calcium intake14.

The consumption of dairy products during childhood is asso-ciated with stronger bones in adulthood. Women who drank at least one glass of milk daily until they turned 25 had significant-ly denser bones as adults than those in the control group who consumed less than one glass of milk per week15. Bone density does not, however, remain stable without regular calcium intake in adulthood, too. Insufficient intake of calcium later in life in-creases bone resorption and the risk of osteoporosis16,17.

There are also some indications that the body uses calcium more efficiently if the calcium dose is small18. It may be more beneficial to divide the daily calcium intake, 800 mg, into several doses of

Folic acid

Thiamine

Magnesium

Potassium

Niacin

Zinc

Selenium

Vitamin D

Iodine

Vitamin B2

Calcium

Phosphorus

Vitamin B12

% of recommended daily intake

Women Men


Summary

• Milk is a source of a variety of vitamins and minerals. It also contains plenty of high-quality protein.

• Dairy products are the most important source of calcium in our diet.

• Sufficient calcium intake throughout life is important in order to attain and maintain strong bones.


e.g. 200 mg instead of having it all at once. Thus, the level of parathyroid hormone (PTH), which stimulates bone resorption, remains lower. According to some studies, calcium and dairy products increase bone density to an equal degree, but the calcium from dairy products seems to have additional beneficial effects on bone geometry and strength19,20. Consuming dairy products with several meals during the day is an efficient way to ensure sufficient intake of calcium, and strong bones.

Don’t lose weight at the expense of your bones

Several studies have indicated that weight loss increases bone resorption21–23. Where the daily intake of calcium has satisfied the recommended 800 mg despite the lower energy intake, weight loss has not affected bone density or increased bone resorption in the trials24–28.

Fat free and low fat dairy products supply a variety of nutrients in a lighter diet that particularly emphasises the importance of the nutritional density of a meal. Nutrient dense food contains large amounts of different vitamins and minerals per unit of energy. Their opposite, are so-called “empty calories”, i.e. food or drink which contains energy but little or no important nut-rients.

During pregnancy, the need for extra energy does not increase in line with the need for protective nutrients, and therefore empty calories should be avoided then, too. Pregnancy and breast-feeding increase the calcium requirement and contribute to a reduction in bone density if calcium intake is insufficient29. Foe-tal bone development requires a total of 25–30 grams of calcium. In early pregnancy, the foetus receives approximately 50 mg of calcium per day from the mother, rising in late pregnancy to as much as 330 mg per day. During breast-feeding, the calcium is drawn from the mother’s reserves to secure sufficient intake for the child. The recommended calcium intake for pregnant and breast-feeding women is slightly higher than normal at 900 mg/day.

References:

1. Barr SI, McCarron DA, Heaney RP et al. Effects of increased consumption of fluid milk on energy and nutrient intake, body weight, and cardio- vascular risk factors in healthy older adults. J Am Diet Assoc 2000; 100:810–7.

2. Ranganathan R, Nicklas TA, Yang SJ et al. The nutritional impact of dairy product consumption on dietary intakes of adults (1995-1996): The Bogalusa Heart Study. J Am Diet Assoc 2005;105:1391–400.

3. O’Neil CE, Nicklas TA, Liu Y et al. The impact of dairy product consumption on nutrient adequacy and weight of Head Start mothers. Public Health Nutrition 2008;12:e1–9.

4. van Staveren WA, Steijns JM, de Groot LCPGM. Dairy products as essen tial contributors of (micro-) nutrients in reference food patterns: an outline for elderly people. J Am Coll Nutr 2008;27:747S–754S.

5. Paturi M, Tapanainen H, Reinivuo H et al. Finravinto 2007 -tutki- mus [in Finnish]. Kansanterveyslaitoksen julkaisuja B 23/2008.

6. National Nutrition Council. Finnish nutrition recommendations [in Finnish]. Helsinki; Edita Prima Oy 2005. http://wwwb.mmm.fi/ ravitsemusneuvottelukunta/FIN11112005.pdf[16.03.2009]

7. Orr J. Milk consumption and the growth of school-children. Lancet 1928:202–3.

8. Leighton G, Clark M. Milk consumption and the growth of school- children. Lancet 1929:40–3.

9. Chan G, Hoffman K, McMurry M. Effects of dairy products on bone and body composition in pubertal girls. J Pediatr 1995;126:551–6.

10. Cadogan J, Eastell R, Jones N et al. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. BMJ 1997;315:1255–60.

11. Merrilees J, Smart E, Gilchrist N et al. Effects of dairy food supplements on bone mineral density in teenage girls. Eur J Nutr 2000;39:256–62.

12. Fiorito LM, Mitchell DC, Smiciklas-Wright H et al. Girls’ calcium intake is associated with bone mineral content during middle childhood. J Nutr 2006;136:1281–6.

13. Moore LL, Bradlee ML, Gao D et al. Effects of average childhood dairy intake on adolescent bone health. J Pediatr 2008;153:667–73.

14. Tang BMP, Eslick GD, Nowson C et al. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370:657–66.

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Treatment of lactose intolerance through diet

Leena Niittynen, M.Sc., DietitianMatti Harju, Ph.D., R&D, Valio Ltd

Lactose occurs naturally only in milk. Besides being found in dairy products, lactose is used in the food industry to improve a product’s texture, flavour or other qualities. Furthermore, the pharmaceuticals industry employs lactose as an excipient. The symptoms caused by lactose could be avoided by eliminating all products which contain milk or dairy products from the diet, but that would be unnecessarily restrictive and affect the intake of important nutrients, such as calcium. Lactose intolerant people should use dairy products as per their own tolerance level. A regular intake of small amounts of lactose may also help the intestines adapt to lactose and reduce future symptoms. Suitable products and amounts thereof can be determined by experimen-tation. There is also a number of low lactose and lactose free dairy products available, especially in Finland.

Sour milk products may be more suitable

Many lactose intolerant people are able to tolerate small amounts of regular dairy products at least when taken with a meal. Solid food slows gastric emptying, providing the lactase enzyme with more time to break down the lactose. It has also been observed that fermented milk products and yoghurt in particular do not cause as great a degree of gastrointestinal symptoms as fresh milk. This is due to yoghurt’s more solid structure and the fact that the lactic acid bacteria used in making fermented milk products participate in breaking down the lactose during fermen-tation and after the product has been consumed. Fermentation decreases dairy product’s lactose content by 20–30%.

A wide range of lactose free and low lactose products in Finland

The food industry has eased the day-to-day life of lactose in-tolerant people through a wide variety of lactose free and low lactose food products. In Finland, Valio’s low lactose HYLA® dairy products were launched in the 1980s. HYLA® stands for HYdro-lysed LActose, which refers to lactose that has been broken down. Low lactose dairy products are suitable for most lactose intolerants, but for the most sensitive individuals Valio has developed completely lactose free dairy products. Matured cheeses are lactose free, too, as their lactose was broken down in the maturation process.

Lactose intolerant people will be able to find the products most suitable for them simply by reading the product information on dairy packages, which notes the lactose content. The list of ingre-dients in other products containing milk includes the milk-based ingredient (milk, milk powder, cream, fermented milk, yoghurt, quark, whey, whey powder, or lactose). At present, low lactose and lactose free alternatives can also be found among many

products that contain milk, such as ready-to-serve meals, bakery products and spreads.

With regard to lactose content, eating out is not usually prob-lematic in Finland, as almost all canteens and restaurants offer lactose free or low lactose alternatives. In other countries the concept of lactose is not as well known, so those who are very sensitive to lactose may have to choose a milk-free option or take a lactase enzyme preparation available at pharmacies. If a lactose intolerant person consumes lactose by mistake, it should be remembered that the symptoms caused by lactose may be unpleasant but are not dangerous.

A solution from the food industry – lactose free products

People who are very sensitive to lactose are not able to tolerate it at all. And for them, Valio has developed a completely lactose free milk. Ten years of research and development have paid off, as the product has exceeded all expectations both in Finland and in international markets.

Old process, new purpose

Chromatographic separation is an industrial process used exten-sively in the sugar industry. Valio originally acquired a chroma-tographic separator to improve the separation of lactose from whey. When the company ceased producing lactose in whey processing in the 1990s, the development of lactose free milk commenced. After years of research and development, it became possible to produce lactose free milk (with less than 0.01% lactose) through chromatography. Unlike HYLA® milk, it tastes exactly like fresh milk as it does not contain as much of the lac-tose hydrolysis biproducts glucose and galactose which are 2–3 times sweeter than lactose.

The extraordinary success of lactose free milk

There were a number of obstacles to the introduction of lactose free milk. The manufacturing process is rather expensive and consumers were not believed to be prepared to pay double the price of regular milk. There were concerns that the product would decrease the sales of Valio’s HYLA® milk. EU legislation means the product cannot be called milk since one of its ingre-dients, lactose, has been removed, and consumers were expected to find the name milk drink strange.

Lactose free milk drink was eventually launched in autumn 2001. The product reached its annual sales target within a couple of months and began its journey to becoming one of


Summary

• Milk is an important source of calcium; hence, a milk-free diet is not recommended as a means to avoid the symptoms of lactose intolerance.

• Many individuals with lactose intolerance tolerate small amounts of ordinary dairy products, especially sour milk products.

• There is a wide variety of low lactose and lactose free products available in Finland.

• Lactose free milk drink and other Valio Zero LactoseTM dairy products suit even the most sensitive lactose intolerants.

Paul

Bru

ck:

Valio’s most significant innovations. Sales of HYLA® milk did not fall, since lactose free milk drink was consumed by people who had given up milk because of their lactose intolerance and who disliked the sweet taste of HYLA® milk.

The positive results achieved in Finland generated interest in the lactose free milk drink around the world. It is already exported to Sweden, Belgium, the Baltic States and Russia. Increased sales made it necessary to develop the manufacturing technology further as well. Based on ultra-filtration and restoration of the salts in milk, the new, more easily licensed method is already

patent protected in many countries. Valio licenses the new manufacturing technology to Switzerland, Spain and South Korea.

The process of developing lactose free milk has been long and challenging but its success has confirmed that the work was not in vain. There is good reason to describe lactose free milk drink an innovation.

Lactose content in a number of food products.

Food product Portion Lactose (g)

Milk 2 dl 10HYLA® milk 2 dl < 1 Zero LactoseTM milk drink 2 dl 0Flavoured yoghurt 2 dl 5–6Ice cream 1 cone 3Matured cheese 2 slices 0Margarine 5 g 0.01Roll, baked with milk 1 roll 0.5Lasagne 300 g 3 Milk chocolate, one piece 10 g 1

Source: Fineli® – Finnish Food Composition Database. www.fineli.fi