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  • Review
  • Open Access

Lactose intolerance and gastrointestinal cow’s milk allergy in infants and children – common misconceptions revisited

  • 1Email author,
  • 2,
  • 3,
  • 4,
  • 5,
  • 5,
  • 6,
  • 7,
  • 8 and
  • 9
World Allergy Organization Journal201710:41

https://doi.org/10.1186/s40413-017-0173-0

  • Received: 2 June 2017
  • Accepted: 15 November 2017
  • Published:

Abstract

Lactose is the main carbohydrate in human and mammalian milk. Lactose requires enzymatic hydrolysis by lactase into D-glucose and D-galactose before it can be absorbed. Term infants express sufficient lactase to digest about one liter of breast milk daily. Physiological lactose malabsorption in infancy confers beneficial prebiotic effects, including the establishment of Bifidobacterium-rich fecal microbiota. In many populations, lactase levels decline after weaning (lactase non-persistence; LNP). LNP affects about 70% of the world’s population and is the physiological basis for primary lactose intolerance (LI). Persistence of lactase beyond infancy is linked to several single nucleotide polymorphisms in the lactase gene promoter region on chromosome 2. Primary LI generally does not manifest clinically before 5 years of age. LI in young children is typically caused by underlying gut conditions, such as viral gastroenteritis, giardiasis, cow’s milk enteropathy, celiac disease or Crohn’s disease. Therefore, LI in childhood is mostly transient and improves with resolution of the underlying pathology. There is ongoing confusion between LI and cow’s milk allergy (CMA) which still leads to misdiagnosis and inappropriate dietary management. In addition, perceived LI may cause unnecessary milk restriction and adverse nutritional outcomes. The treatment of LI involves the reduction, but not complete elimination, of lactose-containing foods. By contrast, breastfed infants with suspected CMA should undergo a trial of a strict cow’s milk protein-free maternal elimination diet. If the infant is not breastfed, an extensively hydrolyzed or amino acid-based formula and strict cow’s milk avoidance are the standard treatment for CMA. The majority of infants with CMA can tolerate lactose, except when an enteropathy with secondary lactase deficiency is present.

Keywords

  • Malabsorption
  • Carbohydrate
  • Enteropathy
  • Cow’s milk allergy
  • Celiac disease
  • Gastroenteritis

Background

Lactose intolerance (LI) is a common gastrointestinal condition which is due to the inability to digest and absorb dietary lactose. Lactose requires hydrolysis by the enzyme lactase into D-glucose and D-galactose before it can be absorbed. About 70% of the world’s population suffer from LI due to a genetically programmed gradual decline in lactase expression after weaning, so-called lactase non-persistence (LNP) [1, 2]. The introduction of dairy farming and regular consumption of cow’s milk over 5000 years ago selected individuals who tolerated lactose-containing foods beyond early childhood [3]. Population genomics suggest that the ability to digest lactose beyond infancy (i.e. lactase persistence) emerged around the time of the Eurasian Bronze Age (3000–1000 B.C) [4]. While regular ingestion of milk and fermented milk products is likely to have improved individuals’ nutritional status, it remains unclear if other clinical benefits have promoted the genetic selection of lactase persistence [1].

LI presents with mild to moderate gastrointestinal symptoms, including abdominal pain, flatulence and diarrhea. Children under 5 years can generally tolerate lactose as primary LI rarely manifests clinically in this age group [5, 6]. However, in regions with a high prevalence of primary LI, the intake of cow’s milk-based products may be unnecessarily restricted. Due to the similarities in the clinical symptoms of gastrointestinal CMA and LI, there is ongoing diagnostic confusion - not only by parents but also amongst health professionals [79]. While transient lactose malabsorption following gastroenteritis is relatively common in children under 2 years [10, 11], more persistent symptoms due to cow’s milk enteropathy are often not recognized [12] and may be inappropriately treated with a lactose-free, cow’s milk protein-containing formula [7]. The following paper aims to provide an overview of the physiology, clinical presentation, differential diagnosis and treatment of LI. It will also address several common misconceptions about LI in infants and young children.

Physiology of lactose absorption

Lactose (β-galactosyl-1,4 glucose) is the main carbohydrate in human and mammalian milk. Human milk contains about 7.5 g/100 mL of lactose, compared to about 5 g/100 mL in cow’s milk and other mammalian milk [13]. A term infant is typically able to digest about 60–70 g of lactose per day, equivalent to one liter of breast milk. Young infants do not absorb all of the ingested lactose from breast milk (physiological lactose malabsorption). Malabsorbed lactose is fermented in the colon to short-chain fatty acids (SCFA), hydrogen (H2), carbon dioxide (CO2) and methane (CH4). Malabsorbed lactose is also converted to lactic acid by enteric bacteria (Streptococcus lactis and others) [14].

Lactase

Lactase-phlorizin hydrolase, commonly called lactase, splits lactose into D-glucose and D-galactose [15, 16]. Lactase is a member of the beta-galactosidase family and is only expressed by mature enterocytes, with its highest expression in the mid-jejunum [17]. The enzyme spans the apical membrane of mature enterocytes and is made up of two identical extracellular 160 kDa polypeptide chains, as well as a short intracytoplasmic part [18].

Pathophysiology of lactose malabsorption

Individuals with LI absorb between 42 and 77% of ingested lactose after a 12.5 g dose, compared to 95% in lactase persisters [19]. The clinical manifestations of LI are due to osmotic fluid shifts into the gut, as well as gas formation and bowel distension. This may present with abdominal pain, flatulence and diarrhea. Several factors influence whether malabsorbed lactose will cause gastrointestinal symptoms, including the dose, food matrix, oro-cecal transit time and fermenting capacity of the fecal microbiota. In individuals with LI, ongoing lactose ingestion may ameliorate diarrhea and flatulence due to the proliferation of lactose-fermenting, non-hydrogen producing bacteria (e.g. Bifidobacteria) [20]. Diarrhea due to LI occurs mainly in infants and young children as this age group lacks the ability to compensate by colonic reabsorption. In older children, reabsorption of fermentation products (e.g. SCFA, lactate) reduces the osmotic load and significantly reduces diarrhea. Diarrhea after smaller amounts of milk should therefore not simply be attributed to LI alone, and other medical causes (e.g. non-IgE-mediated CMA) be considered [21].

Genetics and epidemiology of lactose intolerance

The lactase gene is located on the long arm of chromosome 2 (region 2q21) [22]. Its expression is regulated by a promoter region located upstream from the gene. Maximum lactase expression in enterocytes occurs during the first months of life and declines after weaning [23, 24]. In individuals with LNP, lactase levels gradually fall to about 10–25% compared to those of young infants due to a decrease in mRNA [6, 18].

Several single nucleotide polymorphisms (SNP) have been identified in the promoter region of the lactase gene [25]. The most common polymorphism associated with lactase persistence in Caucasians is characterized by a C > T change at 13910 base pairs upstream of the lactase gene. Several other polymorphisms for lactose persistence have been identified with specific regional differences [2631]. While the C/C13910 genotype is associated with lactose malabsorption, the genotypes C/T and T/T are found in individuals with lactase persistence [2]. Heterozygotes carrying the C/T allele differ in their response to an oral lactose load, compared to C/C and T/T genotypes, suggesting an intermediate phenotype [32].

Lactase persistence is common in people of Northern European, West African or Middle Eastern background. Estimated prevalence figures for primary LI due to LNP are 2–5% in Northern Europe (Scandinavia, Germany, Great Britain), 17% in Finland and Northern France, about 50% in South America and Africa, and between 90 and 100% in Southeast Asia [33]. In North American adults, the rates of LI vary by ethnicity (79% of Indigenous Americans, 75% of African-Americans, 51% of Hispanics, and 21% of Caucasians) [6, 34].

Physiological benefits of lactose in human milk

Lactose in human milk contributes significantly to the daily energy intake of breastfed infants. Due to the required hydrolysis by lactase, there is a delayed and sustained effect on blood glucose levels. Lactose in breast milk is thought to increase the absorption of calcium [35]. As young infants do not absorb all of the lactose from breast milk, malabsorbed lactose acts as a prebiotic [36]. This is associated with increased counts of Bifidobacteria and increased concentrations of SCFA which confer a protective effect on colonic mucosal integrity and have a beneficial effect on early immune development [37].

Definitions and classifications

It is important to distinguish between the terms lactase deficiency, lactose malabsorption and lactose intolerance which are often used interchangeably. ‘Lactase deficiency’ describes the state of reduced lactase expression, compared to term infants. ‘Lactose malabsorption’ indicates that not all ingested lactose was absorbed and that some has reached the large intestine. ‘Lactose intolerance’ is clinically defined as lactose malabsorption with associated gastrointestinal symptoms. There are four main clinical types of LI: developmental lactase deficiency, congenital lactase deficiency (alactasia), lactase non-persistence (LNP) and secondary lactose intolerance (Table 1).
Table 1

Clinical classification of lactose intolerance

Developmental lactase deficiency

Observed in premature infants (less than 34 weeks of gestation) due to temporary lactase deficiency which improves with time. The peak lactase expression is reached at term when an infant typically tolerates up to 60-70 g of lactose per day, corresponding with one liter of breast milk.

Congenital lactase deficiency (alactasia)

Rare and severe autosomal recessive disorder presenting in newborn infants with severe osmotic diarrhea at commencement of breast feeding. Case reports are mainly from Finland and Western Russia. Small intestinal lactase activity is completely absent. The small intestinal mucosa is otherwise normal.

Lactase non-persistence (hypolactasia)

Physiological gradual decline of lactase activity after weaning. This occurs in about 70% of the global population. Significant gastrointestinal symptoms generally do not occur before 5 years of age. The peak onset is in teenagers and young adults. Small amounts of lactose are tolerated by most affected individuals if taken in divided amounts during the day (up to 24 g per day in older children and adults).

Secondary lactose intolerance

May occur as a consequence of small bowel injury due conditions such as viral gastro-enteritis, giardiasis, celiac disease or Crohn’s disease. Rare causes of secondary lactose intolerance include epithelial dysplasia syndromes (e.g. microvillus inclusion disease, tufting enteropathy) which present with severe malabsorption and intestinal failure in early infancy. Infants with glucose-galactose malabsorption have normal lactase activity but present with osmotic diarrhea due to the inability to absorb glucose and galactose (derived from lactose).

Developmental lactase deficiency

Lactase is the last small intestinal disaccharidase to develop during intrauterine development. In premature infants (26–34 weeks’ gestation), lactase activity reaches about 30% of that of term infants (maturational delay) [23]. When commencing breast milk or formula, premature infants may develop clinical signs of lactose malabsorption when exposed to breast milk or formula which are usually transient. A Cochrane review examining the role of enteral lactase supplementation on anthropometric measurements and gastrointestinal symptoms in premature infants found no major clinical benefits [38, 39].

Congenital lactase deficiency (alactasia)

Alactasia is a rare and severe autosomal recessive disorder of the newborn infant [40]. The condition mainly occurs in Finland and Western Russia [41]. Infants present with watery diarrhea, flatulence and failure to thrive after commencing breast milk or formula feeding. This may lead to life-threatening dehydration or electrolyte imbalances. Lactase activity is either completely absent or very low while other duodenal disaccharidases are detected at normal levels [42]. The intestinal epithelium is histologically normal. Several mutations in the lactase gene have been described [41]. Rarely, intestinal epithelial dysplasia syndromes (e.g. microvillus inclusion disease, tufting enteropathy) or defects in the SGLT-1 transporter (e.g. congenital glucose-galactose malabsorption) may mimic congenital lactase deficiency.

Lactase non-persistence

LNP (also called hypolactasia) is the most common cause of LI. While the declince in lactase levels starts soon after weaning, symptoms generally do not manifest before 5 years of age [43]. In an Indonesian study, the prevalence of symptomatic hypolactasia at 3 years of age was 9.1%. The prevalence rose to 28.6% at 5 years, and 73% at 12–14 years of age [44].

Secondary lactose intolerance

Secondary LI occurs as a result of small intestinal villous damage and decreased lactase expression. In young children, the most common causes of secondary LI include viral gastroenteritis [10], giardiasis [45], non-IgE-mediated cow’s milk enteropathy [46], celiac disease [47] and Crohn’s disease [48]. Secondary LI usually resolves within 1–2 months, depending on the underlying gut disorder [49].

Clinical presentation

The clinical presentation of LI differs significantly between infants and older children. Symptoms generally occur within 30–60 min of ingesting lactose-containing foods. Infants with lactose malabsorption are more prone to develop diarrhea, compared to older children and adults. A low fecal pH < 5.5 may cause perianal skin irritation and excoriation. While some infants with secondary LI may experience abdominal pain and distension, infantile colic is generally not caused by LI. Lactose-free formula is therefore thought to be ineffective and is not recommended for the treatment of colic [50].

In older children and adults, symptoms of LI include abdominal pain, bloating, abdominal distension, flatulence, borborygmi and low-grade diarrhea. In a case series of 98 Indonesian adolescents with LI, abdominal pain was the main complaint (64.1%), followed by abdominal distension (22.6%), nausea (15.1%), flatulence (5.7%) and diarrhea (1.9%) [44]. In adolescents and adults, irritable bowel syndrome-like symptoms are often perceived to be due to LI. However, subsequent double-blind challenges have failed to demonstrate a clear benefit of lactose restriction in these patients [51]. LI is therefore thought to be a contributing factor in irritable bowel syndrome, but visceral hyperalgesia and reactions to other fermentable carbohydrates may also be of importance [52].

Laboratory diagnosis

The diagnosis of LI relies on the observation of gastrointestinal symptoms after ingestion of lactose-containing foods, including breast milk, cow’s milk or other mammalian milk. Several diagnostic methods are available to confirm lactose malabsorption. In children, causes of secondary LI should always be considered in the differential diagnosis.

Reducing sugars and pH in stool

Measurement of total and reducing sugars in stool is an indirect test for lactose malabsorption [53]. Apart from lactose, other reducing sugars (e.g. glucose, galactose and fructose) are also detected by this method. The test is therefore not specific for LI. The stool pH in infants with LI is typically below 5.5 to 6.0. The liquid portion of a stool sample should be analyzed. Up to 0.25% of total/reducing sugars is considered normal. In young breastfed infants with physiological lactose malabsorption, concentrations may be higher [54]. The test is not recommended in children older than 2 years of age due to a righ rate of false-negative results.

Lactose breath hydrogen testing

Breath hydrogen testing relies on the detection of exhaled hydrogen after a standard dose of lactose. After an overnight fasting period, baseline hydrogen should be close to 0 parts per million (ppm). Breath samples are taken every 15–30 min for 3 h (from time of the lactose bolus). A rise in exhaled hydrogen by ≥20 ppm from baseline is considered diagnostic [55]. False negative result may occur in the absence of hydrogen producing bacteria, e.g. after recent antibiotic treatment. For this reason, a positive control test with lactulose (a non-absorbable synthetic disaccharide) is required for validation of a negative result to lactose. Another method of reducing the risk of false-negative results is the co-measurement of exhaled methane [56, 57]. Both hydrogen and methane are bacterial breakdown products from lactose. Exhaled methane levels rise after the bacterial fermentation of malabsorbed lactose, even if hydrogen-producing bacteria are absent. A rise in exhaled methane by ≥10 ppm from baseline is considered evidence of lactose malabsorption [55]. The correlation of breath hydrogen testing (BHT) results with clinical symptoms is variable. While low-grade diarrhea and flatulence during the BHT are highly specific symptoms, abdominal pain on its own should not be attributed to LI [58].

Duodenal disaccharidases

Lactase and other duodenal disaccharidases (sucrase, maltase, isomaltase) are measured in duodenal biopsies which can be obtained during gastroscopy. In cases of cow’s milk enteropathy or celiac disease with villous damage, lactase concentrations are typically reduced while sucrase levels are sufficient [47, 59]. In infants with congenital alactasia, lactase is either very low or completely absent while the histological appearance of the duodenum is normal [42].

Genetic diagnosis of hypolactasia

Genetic testing allows the prediction of hypolactasia, even before symptoms are present. Commercial assays are based on the C > T13910 polymorphism which is associated with lactase persistence in Caucasians. Testing for other SNPs may also become available. The clinical usefulness of this test is controversial as it may lead to unnecessary lactose restriction before symptoms are present.

Treatment of lactose intolerance

In infants with LI, breast-feeding should be continued. In formula-fed infants, a limited trial of lactose-free formula may be indicated, e.g. following viral gastroenteritis. In children with persistent diarrhea following acute gastroenteritis, lactose restriction has been shown to shorten the duration of gastrointestinal symptoms [11]. Reintroduction of lactose-containing formula or foods should be attempted after 2–4 weeks, as tolerated. In infants with celiac disease or other small intestinal pathology, lactose restriction may be required until the underlying condition has resolved or been adequately treated. This also applies to infants with non-IgE-mediated CMA and enteropathy. In these infants, a lactose-containing EHF is often tolerated after the gut pathology has resolved on a hypoallergenic elimination diet [46].

In individuals with LI, lactose-containing foods should be reduced but do not need to be eliminated completely. Adolescents and adults with hypolactasia tolerate up to 12-24 g of lactose daily, if taken in divided amounts. Consuming milk with a meal and in divided doses improves overall tolerance as it slows the release of lactose in the small intestine. Dietary lactose is mainly derived from fresh cow’s milk and other milk-based dairy products (e.g. yoghurt, ice cream). The content in yoghurt is lower than in milk due to breakdown of lactose by lactose-fermenting bacteria. As lactose is mainly found in the watery portion of milk, hard cheese only contains small amounts (0.1 to 0.9 g in 30 g of hard cheese), and the lactose content of butter is negligible [21]. Some medications contain lactose as a carrier, but amounts are rarely sufficient to be clinically relevant [60].

Treatment of infants with congenital lactose deficiency (alactasia)

In infants with congenital lactase deficiency, breast milk or lactose-containing formula cause persistent watery diarrhea and growth failure. In this situation, breast feeding can generally not be sustained. Infants with congenital lactase deficiency require a change to a lactose-free formula. If recognized and treated early, infants with congenital lactase deficiency achieve normal growth and development [61]. Lactose restriction needs to be continued for life. However, older children and adults may tolerate small amounts of dietary lactose, depending on the disease severity.

Lactase supplementation

In children and adults with LI, oral lactase supplements have been shown to ameliorate the severity of gastrointestinal symptoms after a lactose challenge [62, 63]. Ingested lactase is easily broken down by gastric acid and inactivated. Lactase treatment in infants is therefore only effective if added to expressed breast milk or formula for several hours before feeding [64].

Inappropriate use of lactose-free or lactose-reduced formula in infants with CMA

A recent survey in Northern Ireland (2012–2014) assessed formula prescription patterns in infants with likely non-IgE-mediated CMA. The survey found that thickened anti-regurgitation formula, lactose-reduced partially hydrolyzed formula or lactose-free, cow’s milk protein-containing formulas were commonly prescribed in infants with symptoms suggestive of non-IgE-mediated CMA [7]. The survey was repeated after the implementation of active education and national feeding guidelines [7]. Following the educational interventions, the use of EHF and AAF increased by 63%, while the use of alternative treatments was reduced by 44.6%. Overall, the recognition of CMA increased from 3.4% to 9.8% of treated infants. This study demonstrates both the need for health care provider education on gastrointestinal CMA, as well as the usefulness of educational campaigns and national treatment guidelines.

Role of extensively hydrolyzed formula with lactose in infants with CMA

Extensively hydrolyzed formula (EHF), the first-line treatment for formula-fed infants with CMA, was initially designed to treat malabsorption. For this reason, early generation EHF were typically lactose-free and short peptide-based formulas with a high content of medium chain triglycerides (MCT). In recent years, lactose has been added to extensively hydrolyzed formula (EHF). Lactose in hydrolyzed formula has been shown to increase the absorption of calcium, when compared to lactose-free formula [35]. Highly purified lactose is tolerated well by cow’s milk-allergic infants [65, 66]. Lactose restriction is only warranted in infants with CMA if an enteropathy with secondary lactase deficiency is present (Fig. 1). Lactose may cautiously be reintroduced after about 1–2 months, once symptoms have resolved and small intestinal lactase activity been restored. Table 2 summarizes the various subtypes of IgE- and non-IgE-mediated CMA in relation to lactose restriction.
Fig. 1
Fig. 1

Clinical overlap between cow’s milk allergy and lactose intolerance

Table 2

Lactose restriction in cow’s milk allergic infants

Type of cow’s milk allergy (CMA)

Need for lactose restriction

IgE-mediated CMA / anaphylaxis

NO a

Cow’s milk protein-induced enteropathy

YES b

Cow’s milk protein-induced enterocolitis syndrome (FPIES)

NO

Cow’s milk protein-induced proctocolitis

NO

CMA-associated gastro-esophageal reflux disease

NO

CMA-associated constipation

NO

CMA-associated eczema

NO

a For formula-fed infants with non-anaphylactic IgE-mediated CMA, a lactose-containing extensively hydrolyzed formula is suitable [60]. In infants with a history of anaphylaxis to cow’s milk protein, an amino acid-based formula is recommended. No lactose-containing amino acid-based formula is currently available

b For formula-fed infants with cow’s milk protein-induced enteropathy, a lactose-free extensively hydrolyzed formula or amino acid-based formula are considered the first line treatment, depending on clinical features and severity [60]. Lactose may be tolerated later in the treatment course after intestinal mucosal repair has been achieved on a cow’s milk protein-free diet

The addition of lactose slightly increases the sweetness of EHF which is thought to improve the overall palatability. This reduces the risk of taste aversion and formula refusal, particularly by older infants [67]. In addition, recent studies have demonstrated that lactose in EHF confers prebiotic benefits in infants with CMA [36, 68]. The addition of lactose to EHF significantly increased the counts of Bifidobacteria, lactic acid bacteria and decreased Bacteroides and Clostridia, compared to lactose-free EHF [36]. The same study also demonstrated a positive effect on the fecal metabolome with increased concentrations of SCFA (mainly acetic and butyric acid). These prebiotic effects of lactose are likely to have a positive effects on early immune development [69]. The authors speculate that lactose may also play a role in the acquisition of tolerance, although no data to this effect are currently available [36]. Given the positive effects on fecal microbiome and metabolome, lactose-containing EHF may offer clinical and immunological benefits in the treatment of infants with CMA.

Nutritional adequacy of lactose-free diets

Over the past decade there has been a sharp decline in the consumption of fresh cow’s milk and increased consumption of lactose-free milk and cereal milks in the community [70]. Parents may restrict milk products in their children due to unfounded concerns about LI or CMA. A study of Swedish children and adolescents assessed the likelihood of milk avoidance according to genetic lactase persister status [71]. While LI in adolescents did not affect vitamin D levels or anthropometric variables, it was associated with reduced milk and calcium intakes, compared to those who tolerated lactose (OR 3.2; 95% CI 1.5, 7.3) [71].

The main adverse health effects of LI occur as a result of milk avoidance and reduced calcium intakes. Avoidance of dairy products may lead to nutritional rickets in young children [72], as well as low bone mineral density and increased fracture risk later in life [73]. Calcium intake is a marker for dietary adequacy and closely correlates with the intake of other micronutrients [74]. Calcium absorption in individuals with LI is normal, which means that calcium can be administered as an oral supplement in non-dairy formats [75].

Conclusion

Confusion between CMA and LI may lead to a delayed diagnosis of CMA, as well as inappropriate dietary interventions. Primary LI in children under 5 years is uncommon, even in regions with a high prevalence of primary hypolactasia. In young children with LI, an underlying gut condition should therefore always be considered in the diagnostic process. In these cases, lactose restriction is only required until the underlying condition has either resolved or been treated. Gastrointestinal CMA represents the main differential diagnosis to LI in infancy. Contrary to common belief, most infants with CMA can tolerate dietary lactose. Lactose-containing EHF offers potential benefits in the treatment of formula-fed infants with CMA due to prebiotic effects on fecal microbiome and metabolome. Evidence-based educational health campaigns are needed to address the knowledge gaps and misconceptions around LI and CMA in the community.

Abbreviations

AAF: 

Amino acid-based formula

CMA: 

Cow’s milk allergy

EHF: 

Extensively hydrolyzed formula

LI: 

Lactose intolerance

LNP: 

Lactase non-persistence

MCT: 

Medium chain triglyceride

ppm: 

Parts per million

SCFA: 

Short chain fatty acid

SNP: 

Single nucleotide polymorphism

Declarations

Funding

The two meetings of the expert panel in 2016 and 2017 were funded by an unrestricted educational grant from Nestlé Health Science, Switzerland.

Availability of data and materials

Not applicable, review paper only.

Authors’ contributions

All authors have equally contributed to the manuscript and have reviewed the final version of the manuscript.

Ethics approval and consent to participate

Not required.

Consent for publication

All authors have reviewed the manuscript and have provided their consent for publication.

Competing interests

Dr. Ralf Heine has been a member of the scientific advisory boards of Nestlé Health Science / Nestlé Nutrition Institute, Australia/Oceania and Nutricia Australia. He has received honoraria from industry for educational activities. All authors have received reimbursement for travel expenses for this project from Nestlé Health Science, Switzerland. The authors otherwise declare that they have no competing interests.

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Authors’ Affiliations

(1)
Murdoch Childrens Research Institute, Melbourne, Australia
(2)
Al Adan Hospital, Ministry of Health, Kuwait City, Kuwait
(3)
Rainbow Children’s Hospital, Banjara Hills, Hyderabad, India
(4)
Philippine Society of Allergy, Asthma & Immunology, Philippine Medical Association, Quezon City, Philippines
(5)
Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
(6)
Universidad National Autonoma de México, Hospital Infantil Privado Star Médica, Polanco, Mexico City, Mexico
(7)
Chualalongkorn University, Bangkok, Thailand
(8)
KK Women’s and Children’s Hospital and Yong Loo Lin School of Medicine and Duke-NUS Medical School, Singapore, Singapore
(9)
University of the Philippines, Philippine General Hospital, Manila, Philippines

References

  1. Wahlqvist ML. Lactose nutrition in lactase nonpersisters. Asia Pac J Clin Nutr. 2015;24(Suppl 1):S21–5.PubMedGoogle Scholar
  2. Harvey CB, Hollox EJ, Poulter M, Wang Y, Rossi M, Auricchio S, Iqbal TH, Cooper BT, Barton R, Sarner M, Korpela R, Swallow DM. Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism. Ann Hum Genet. 1998;62:215–23.View ArticlePubMedGoogle Scholar
  3. Simoons FJ. Primary adult lactose intolerance and the milking habit: a problem in biologic and cultural interrelations. II. A culture historical hypothesis. Am J Dig Dis. 1970;15:695–710.View ArticlePubMedGoogle Scholar
  4. Allentoft ME, Sikora M, Sjögren KG, Rasmussen S, Rasmussen M, Stenderup J, Damgaard PB, Schroeder H, Ahlström T, Vinner L, Malaspinas AS, Margaryan A, Higham T, Chivall D, Lynnerup N, Harvig L, Baron J, Della Casa P, Dabrowski P, Duffy PR, Ebel AV, Epimakhov A, Frei K, Furmanek M, Gralak T, Gromov A, Gronkiewicz S, Grupe G, Hajdu T, Jarysz R, Khartanovich V, Khokhlov A, Kiss V, Kolář J, Kriiska A, Lasak I, Longhi C, McGlynn G, Merkevicius A, Merkyte I, Metspalu M, Mkrtchyan R, Moiseyev V, Paja L, Palfi G, Pokutta D, Pospieszny Ł, Price TD, Saag L, Sablin M, Shishlina N, Smrčka V, Soenov VI, Szeverényi V, Tóth G, Trifanova SV, Varul L, Vicze M, Yepiskoposyan L, Zhitenev V, Orlando L, Sicheritz-Pontén T, Brunak S, Nielsen R, Kristiansen K, Willerslev E. Population genomics of Bronze Age Eurasia. Nature. 2015;522:167–72.View ArticlePubMedGoogle Scholar
  5. Lebenthal E, Antonowicz I, Shwachman H. Correlation of lactase activity, lactose tolerance and milk consumption in different age groups. Am J Clin Nutr. 1975;28:595–600.PubMedGoogle Scholar
  6. Welsh JD, Poley JR, Bhatia M, Stevenson DE. Intestinal disaccharidase activities in relation to age, race, and mucosal damage. Gastroenterology. 1978;75:847–55.PubMedGoogle Scholar
  7. Wauters L, Brown T, Venter C, Dziubak R, Meyer R, Brogan B, Walsh J, Fox AT, Shah N. Cow's milk allergy prescribing is influenced by regional and National Guidance. J Pediatr Gastroenterol Nutr. 2016;62:765–70.View ArticlePubMedGoogle Scholar
  8. Grimheden P, Anderlid BM, Gåfvels M, Svahn J, Grahnquist L. Lactose intolerance in children is an overdiagnosed condition. Risk of missing intestinal diseases such as IBD and celiac disease. Läkartidningen. 2012;109:218–21.Google Scholar
  9. Walsh J, Meyer R, Shah N, Quekett J, Fox AT. Differentiating milk allergy (IgE and non-IgE mediated) from lactose intolerance: understanding the underlying mechanisms and presentations. Br J Gen Pract. 2016;66:e609–11.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Davidson GP, Goodwin D, Robb TA. Incidence and duration of lactose malabsorption in children hospitalized with acute enteritis: study in a well-nourished urban population. J Pediatr. 1984;105:587–90.View ArticlePubMedGoogle Scholar
  11. MacGillivray S, Fahey T, McGuire W. Lactose avoidance for young children with acute diarrhoea. Cochrane Database Syst Rev. 2013:CD005433.Google Scholar
  12. Koletzko S, Heine RG. Non-IgE mediated cow's milk allergy in EuroPrevall. Allergy. 2015;70:1679–80.View ArticlePubMedGoogle Scholar
  13. Wojcik KY, Rechtman DJ, Lee ML, Montoya A, Medo ET. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc. 2009;109:137–40.View ArticlePubMedGoogle Scholar
  14. Bissett DL, Anderson RL. Lactose and D-galactose metabolism in group N streptococci: presence of enzymes for both the D-galactose 1-phosphate and D-tagatose 6-phosphate pathways. J Bacteriol. 1974;117:318–20.PubMedPubMed CentralGoogle Scholar
  15. Dahlqvist A. Intestinal carbohydrases of a new-born pig. Nature. 1961;190:31–2.View ArticlePubMedGoogle Scholar
  16. Dahlqvist A, Hammond JB, Crane RK, Dunphy JV, Littman A. Intestinal lactase deficiency and lactose intolerance in adults. Preliminary Report Gastroenterology. 1963;45:488–91.PubMedGoogle Scholar
  17. Auricchio S, Rubino A, Muerset G. Intestinal glycosidase activities in the human embryo, fetus, and newborn. Pediatrics. 1965;35:944–54.PubMedGoogle Scholar
  18. Norén O, Sjöström H. Structure, biosynthesis and regulation of lactase-phlorizin hydrolase. Scand J Nutr. 2001;45:156–60.Google Scholar
  19. Bond JH, Levitt MD. Quantitative measurement of lactose absorption. Gastroenterology. 1976;70:1058–62.PubMedGoogle Scholar
  20. Hertzler SR, Savaiano DA. Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. Am J Clin Nutr. 1996;64:232–6.PubMedGoogle Scholar
  21. Levitt M, Wilt T, Shaukat A. Clinical implications of lactose malabsorption versus lactose intolerance. J Clin Gastroenterol. 2013;47:471–80.View ArticlePubMedGoogle Scholar
  22. Harvey CB, Fox MF, Jeggo PA, Mantei N, Povey S, Swallow DM. Regional localization of the lactase-phlorizin hydrolase gene, LCT, to chromosome 2q21. Ann Hum Genet. 1993;57:179–85.View ArticlePubMedGoogle Scholar
  23. Antonowicz I, Lebenthal E. Developmental pattern of small intestinal enterokinase and disaccharidase activities in the human fetus. Gastroenterology. 1977;72:1299–303.PubMedGoogle Scholar
  24. Buller HA, Van Wassenaer AG, Raghavan S, Montgomery RK, Sybicki MA, Grand RJ. New insights into lactase and glycosylceramidase activities of rat lactase-phlorizin hydrolase. Am J Phys. 1989;257:G616–23.Google Scholar
  25. Wang Y, Harvey CB, Hollox EJ, Phillips AD, Poulter M, Clay P, Walker-Smith JA, Swallow DM. The genetically programmed down-regulation of lactase in children. Gastroenterology. 1998;114:1230–6.View ArticlePubMedGoogle Scholar
  26. Bulhoes AC, Goldani HA, Oliveira FS, Matte US, Mazzuca RB, Silveira TR. Correlation between lactose absorption and the C/T-13910 and G/A-22018 mutations of the lactase-phlorizin hydrolase (LCT) gene in adult-type hypolactasia. Braz J Med Biol Res. 2007;40:1441–6.View ArticlePubMedGoogle Scholar
  27. Kuchay RA, Anwar M, Thapa BR, Mahmood A, Mahmood S. Correlation of G/a −22018 single-nucleotide polymorphism with lactase activity and its usefulness in improving the diagnosis of adult-type hypolactasia among north Indian children. Genes Nutr. 2013;8:145–51.View ArticlePubMedGoogle Scholar
  28. Xu L, Sun H, Zhang X, Wang J, Sun D, Chen F, Bai J, Fu S. The -22018A allele matches the lactase persistence phenotype in northern Chinese populations. Scand J Gastroenterol. 2010;45:168–74.View ArticlePubMedGoogle Scholar
  29. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L. Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet. 2008;82:57–72.View ArticlePubMedPubMed CentralGoogle Scholar
  30. Macholdt E, Slatkin M, Pakendorf B, Stoneking M. New insights into the history of the C-14010 lactase persistence variant in eastern and southern Africa. Am J Phys Anthropol. 2015;156:661–4.View ArticlePubMedGoogle Scholar
  31. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M, Ibrahim M, Omar SA, Lema G, Nyambo TB, Ghori J, Bumpstead S, Pritchard JK, Wray GA, Deloukas P. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet. 2007;39:31–40.View ArticlePubMedGoogle Scholar
  32. Dzialanski Z, Barany M, Engfeldt P, Magnuson A, Olsson LA, Nilsson TK. Lactase persistence versus lactose intolerance: is there an intermediate phenotype? Clin Biochem. 2016;49:248–52.View ArticlePubMedGoogle Scholar
  33. Itan Y, Jones BL, Ingram CJ, Swallow DM, Thomas MG. A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evol Biol. 2010;10:36.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Scrimshaw NS, Murray EB. The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr. 1988;48:1079–159.PubMedGoogle Scholar
  35. Abrams SA, Griffin IJ, Davila PM. Calcium and zinc absorption from lactose-containing and lactose-free infant formulas. Am J Clin Nutr. 2002;76:442–6.PubMedGoogle Scholar
  36. Francavilla R, Calasso M, Calace L, Siragusa S, Ndagijimana M, Vernocchi P, Brunetti L, Mancino G, Tedeschi G, Guerzoni E, Indrio F, Laghi L, Miniello VL, Gobbetti M, De Angelis M. Effect of lactose on gut microbiota and metabolome of infants with cow's milk allergy. Pediatr Allergy Immunol. 2012;23:420–7.View ArticlePubMedGoogle Scholar
  37. West CE, Renz H, Jenmalm MC, Kozyrskyj AL, Allen KJ, Vuillermin P, Prescott SL, in-FLAME Microbiome Interest Group. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015;135:3–13.Google Scholar
  38. Tan-Dy CR, Ohlsson A. Lactase treated feeds to promote growth and feeding tolerance in preterm infants. Cochrane Database Syst Rev. 2005:CD004591.Google Scholar
  39. Erasmus HD, Ludwig-Auser HM, Paterson PG, Sun D, Sankaran K. Enhanced weight gain in preterm infants receiving lactase-treated feeds: a randomized, double-blind, controlled trial. J Pediatr. 2002;141:532–7.View ArticlePubMedGoogle Scholar
  40. Diekmann L, Pfeiffer K, Naim HY. Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. BMC Gastroenterol. 2015;15:36.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Torniainen S, Freddara R, Routi T, Gijsbers C, Catassi C, Höglund P, Savilahti E, Järvelä I. Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD). BMC Gastroenterol. 2009;9:8.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Asp NG, Dahlqvist A, Kuitunen P, Launiala K, Visakorpi JK. Complete deficiency of brush-border lactase in congenital lactose malabsorption. Lancet. 1973;2:329–30.View ArticlePubMedGoogle Scholar
  43. Rasinpera H, Savilahti E, Enattah NS, Kuokkanen M, Totterman N, Lindahl H, Järvelä I, Kolho KL. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut. 2004;53:1571–6.View ArticlePubMedPubMed CentralGoogle Scholar
  44. Hegar B, Widodo A. Lactose intolerance in Indonesian children. Asia Pac J Clin Nutr. 2015;24(Suppl 1):S31–40.PubMedGoogle Scholar
  45. Swiatkowski E, Socha J. Lactose-intolerance and hypolactasia in children with giardiasis. J Pediatr Gastroenterol Nutr. 1990;11:424–5.View ArticlePubMedGoogle Scholar
  46. Heine RG. Pathophysiology, diagnosis and treatment of food protein-induced gastrointestinal diseases. Curr Opin Allergy Clin Immunol. 2004;4:221–9.View ArticlePubMedGoogle Scholar
  47. Prasad KK, Thapa BR, Nain CK, Sharma AK, Singh K. Brush border enzyme activities in relation to histological lesion in pediatric celiac disease. J Gastroenterol Hepatol. 2008;23:e348–52.View ArticlePubMedGoogle Scholar
  48. von Tirpitz C, Kohn C, Steinkamp M, Geerling I, Maier V, Moller P, Adler G, Reinshagen M. Lactose intolerance in active Crohn's disease: clinical value of duodenal lactase analysis. J Clin Gastroenterol. 2002;34:49–53.View ArticlePubMedGoogle Scholar
  49. Heyman MB, Committee on N. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006;118:1279–86.View ArticlePubMedGoogle Scholar
  50. Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, van Geldrop WJ, Neven AK. Effectiveness of treatments for infantile colic: systematic review. BMJ. 1998;316:1563–9.View ArticlePubMedPubMed CentralGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. Staudacher HM, Whelan K, Irving PM, Lomer MC. Comparison of symptom response following advice for a diet low in fermentable carbohydrates (FODMAPs) versus standard dietary advice in patients with irritable bowel syndrome. J Hum Nutr Diet. 2011;24:487–95.View ArticlePubMedGoogle Scholar
  53. Caballero B, Solomons NW, Torun B. Fecal reducing substances and breath hydrogen excretion as indicators of carbohydrate malabsorption. J Pediatr Gastroenterol Nutr. 1983;2:487–90.View ArticlePubMedGoogle Scholar
  54. Counahan R, Walker-Smith J. Stool and urinary sugars in normal neonates. Arch Dis Child. 1976;51:517–20.View ArticlePubMedPubMed CentralGoogle Scholar
  55. Rezaie A, Buresi M, Lembo A, Lin H, McCallum R, Rao S, Schmulson M, Valdovinos M, Zakko S, Pimentel M. Hydrogen and methane-based breath testing in gastrointestinal disorders: the north American consensus. Am J Gastroenterol. 2017;112:775–84.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Moran S, Mina A, Duque X, Anaya S, San-Martin U, Yanez P, Rodriguez-Leal G. Prevalence of lactose malabsorption in Mexican children: importance of measuring methane in expired air. Arch Med Res. 2013;44:291–5.View ArticlePubMedGoogle Scholar
  57. Medow MS, Glassman MS, Schwarz SM, Newman LJ. Respiratory methane excretion in children with lactose intolerance. Dig Dis Sci. 1993;38:328–32.View ArticlePubMedGoogle Scholar
  58. Glatstein M, Reif S, Scolnik D, Rom L, Yerushalmy-Feler A, Dali-Levy M, Cohen S. Lactose breath test in children: relationship between symptoms during the test and test results. Am J Ther. 2016; epub ahead of print.Google Scholar
  59. Nieminen U, Kahri A, Savilahti E, Farkkila MA. Duodenal disaccharidase activities in the follow-up of villous atrophy in coeliac disease. Scand J Gastroenterol. 2001;36:507–10.View ArticlePubMedGoogle Scholar
  60. Montalto M, Gallo A, Santoro L, D'Onofrio F, Curigliano V, Covino M, Cammarota G, Grieco A, Gasbarrini A, Gasbarrini G. Low-dose lactose in drugs neither increases breath hydrogen excretion nor causes gastrointestinal symptoms. Aliment Pharmacol Ther. 2008;28:1003–12.View ArticlePubMedGoogle Scholar
  61. Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency. A clinical study on 16 patients. Arch Dis Child. 1983;58:246–52.View ArticlePubMedPubMed CentralGoogle Scholar
  62. Sanders SW, Tolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactose-intolerant subjects. Clin Pharm. 1992;11:533–8.PubMedGoogle Scholar
  63. Medow MS, Thek KD, Newman LJ, Berezin S, Glassman MS, Schwarz SM. Beta-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child. 1990;144:1261–4.PubMedGoogle Scholar
  64. Chew F, Villar J, Solomons NW, Figueroa R. In vitro hydrolysis with a beta-galactosidase for treatment of intolerance to human milk in very low birthweight infants. Acta Paediatr Scand. 1988;77:601–2.View ArticlePubMedGoogle Scholar
  65. Niggemann B, von Berg A, Bollrath C, Berdel D, Schauer U, Rieger C, Haschke-Becher E, Wahn U. Safety and efficacy of a new extensively hydrolyzed formula for infants with cow's milk protein allergy. Pediatr Allergy Immunol. 2008;19:348–54.View ArticlePubMedGoogle Scholar
  66. Vandenplas Y, Steenhout P, Planoudis Y, Grathwohl D, Althera SG. Treating cow's milk protein allergy: a double-blind randomized trial comparing two extensively hydrolysed formulas with probiotics. Acta Paediatr. 2013;102:990–8.View ArticlePubMedGoogle Scholar
  67. Miraglia Del Giudice M, D'Auria E, Peroni D, Palazzo S, Radaelli G, Comberiati P, Galdo F, Maiello N, Riva E. Flavor, relative palatability and components of cow's milk hydrolysed formulas and amino acid-based formula. Ital J Pediatr. 2015;41:42.View ArticlePubMedPubMed CentralGoogle Scholar
  68. Szilagyi A, Shrier I, Heilpern D, Je J, Park S, Chong G, Lalonde C, Cote LF, Lee B. Differential impact of lactose/lactase phenotype on colonic microflora. Can J Gastroenterol. 2010;24:373–9.View ArticlePubMedPubMed CentralGoogle Scholar
  69. West CE, Jenmalm MC, Prescott SL. The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin Exp Allergy. 2015;45:43–53.View ArticlePubMedGoogle Scholar
  70. Zingone F, Bucci C, Iovino P, Ciacci C. Consumption of milk and dairy products: facts and figures. Nutrition. 2017;33:322–5.View ArticlePubMedGoogle Scholar
  71. Almon R, Sjöström M, Nilsson TK. Lactase non-persistence as a determinant of milk avoidance and calcium intake in children and adolescents. J Nutr Sci. 2013;2:e26.View ArticlePubMedPubMed CentralGoogle Scholar
  72. Fox AT, Du Toit G, Lang A, Lack G. Food allergy as a risk factor for nutritional rickets. Pediatr Allergy Immunol. 2004;15:566–9.View ArticlePubMedGoogle Scholar
  73. Doulgeraki AE, Manousakis EM, Papadopoulos NG. Bone health assessment of food allergic children on restrictive diets: a practical guide. J Pediatr Endocrinol Metab. 2017;30:133–9.View ArticlePubMedGoogle Scholar
  74. Heaney RP. Dairy intake, dietary adequacy, and lactose intolerance. Adv Nutr. 2013;4:151–6.View ArticlePubMedPubMed CentralGoogle Scholar
  75. Cochet B, Jung A, Griessen M, Bartholdi P, Schaller P, Donath A. Effects of lactose on intestinal calcium absorption in normal and lactase-deficient subjects. Gastroenterology. 1983;84:935–40.PubMedGoogle Scholar

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