Lactose is a disaccharide composed of one glucose unit and one galactose unit linked by a β-1,4-glycosidic bond; it is the main sugar naturally present in mammalian milk and accounts for approximately 4.8% of the total content of cow’s milk.1,2 As a natural component, lactose is found exclusively in milk and dairy products and is the only disaccharide of animal origin.3 For its digestion, lactose requires the action of the lactase enzyme, a glycoprotein located in the brush border of the enterocytes of the small bowel.4 Lactase activity decreases naturally in most mammals after weaning, including approximately 75% of the global human population.5,6 When significant amounts of milk or dairy products are consumed, the absence of lactase (alactasia), the decrease in its production (lactase nonpersistence [LNP]), or reduced enzymatic activity (hypolactasia) cause adverse reactions that are colloquially grouped as lactose ingestion-related disorders (LIRDs).7,8 LIRDs constitute one of the most prevalent gastrointestinal problems worldwide and are a common diagnosis in contemporary clinical practice.7 In Mexico, where the genetic diversity of the population reflects a complex mixture of European, Native, and African ancestors, there is an elevated prevalence of these disorders.9–11 To avoid unnecessary dietary restrictions based on misconceptions or self-diagnoses made with no objective evidence, healthcare professionals face the challenge of distinguishing between lactose maldigestion and lactose intolerance mediated by sensory or psychologic mechanisms. In addition, the lack of standardization in the use of diagnostic tests, as well as the lack of knowledge of their limitations and scope, contribute to fragmented and often inefficient care. In such a scenario, the Asociación Mexicana de Gastroenterología (AMG) has developed the “Clinical Guideline for the Diagnosis and Treatment of Lactose Ingestion-Related Disorders”, whose aim is to provide clear, updated recommendations based on high-quality scientific evidence. The present guideline seeks not only to optimize the diagnosis of LIRDs, but also to provide a clinical framework that enables the different manifestations of lactose ingestion to be differentiated and adequately treated, thus contributing to more effective personalized care.

The Delphi methodology, as previously described, was utilized for developing the present guideline.12 Three coordinators (MAB, JMRT, and LFUD) were designated and 15 national experts (gastroenterologists, pediatric gastroenterologists, and clinical nutritionists) were invited to participate and divided into three working groups: 1) epidemiology and definitions, 2) diagnosis, and 3) treatment. The coordinators carried out a comprehensive search in the following databases: CENTRAL (The Cochrane Central Register of Controlled Trials), MEDLINE (PubMed), EMBASE (Ovid), LILACS, CINAHL, BioMed Central, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). The search covered the timeline from January 1, 2010, to January 31, 2025. The search criteria included the following terms: “lactose” combined with the terms: “intolerance”, “definitions”, “sensitivity”, “epidemiology”, “Mexico”, “prevalence”, “hypersensitivity”, “tests”, “diagnosis”, “breath”, “gaxilose”, “symptoms”, “diet”, “lactase”, “maldigestion”; “deficient digestion”, “malabsorption”, “reviews”, “guideline”, and “meta-analysis”. Each coordinator led a working group, convening virtual meetings with the respective members to propose and formulate the statements. At this first stage, 26 statements were suggested that underwent a first anonymous electronic vote (from March 15 to April 15, 2025), to evaluate the content and wording of the statements. The participants voted, using a Likert scale, as follows: a) in complete agreement, b) in partial agreement, c) uncertain, d) in partial disagreement, and e) in complete disagreement. Once the first voting round was concluded, the coordinators made the corresponding modifications. The statements that reached more than 75% agreement were retained and those with more than 75% disagreement were eliminated.12 The statements with <75% agreement and ≤75% disagreement were reviewed and restructured. During the initial phase, 14 statements were approved, 11 were revised for a second vote, one was eliminated and one new statement was proposed, resulting in 26 statements that were submitted to a second anonymous electronic vote (from April 30 to May 15, 2025). Based on the comments received (from May 15 to March 30, 2025), three statements that did not reach 75% agreement were modified by the coordinators. On June 5, at an in-person meeting (AMG southern regional reunion) in Oaxaca, Oaxaca, the 26 statements were reviewed. During the in-person meeting, the statements that reached >75% agreement were ratified. The statements that did not reach said threshold were discussed in an effort to arrive at a consensus. If none was reached, the statements were eliminated or submitted to a new vote. The coordinators then formulated the final recommendations, according to the GRADE system (Quality of Evidence and Strength of the Recommendation).13 In the GRADE framework, the quality of evidence is not graded solely by study design or methodology, but also on a clearly formulated question and its corresponding clinical outcome,14 classifying the quality of the evidence as high, moderate, low, or very low, with a strength of the recommendation as strong or weak, for or against the intervention or statement. Importantly, the strength of the recommendation was established only in the context of diagnostic tests and therapeutic interventions. As shown in Table 1, the GRADE system utilizes uppercase letter codes for the quality of evidence, followed by a number indicating the strength of the recommendation, for or against the intervention. Once the consensus statements were agreed upon, the coordinators prepared the present manuscript, which was reviewed and approved by all members of the consensus panel.

1. In some individuals, the consumption of milk or its derivatives may cause adverse reactions, such as lactose intolerance (LI) or cow’s milk protein allergy, through different pathophysiologic mechanisms that must be appropriately identified.

Agreement percentage: 100% in complete agreement.

In humans, milk consumption normally extends beyond the natural breastfeeding period. We are the only species that incorporates milk into diet on a daily basis. Because of the elevated nutritional value of milk and its derivatives, they are consumed practically worldwide. Milk is a complete food that provides fat, protein, minerals, vitamins, and carbohydrates. Enzymes intervene in the digestive process of milk, converting complex products into simple compounds that are then absorbed and pass into the bloodstream. Lactase, or lactase-phlorizin hydrolase, is an enzyme located in the brush border of the enterocytes of the small bowel and is responsible for the hydrolysis of dietary lactose in milk.6,15 Lactase has a typical activity pattern throughout the life of mammals. It is detectable in the fetal intestine from the eighth week of gestation, gradually increasing up to week 34 at a much higher rate until birth, when it reaches its maximum expression. Enzyme activity is two to four-times higher in the neonate than in children between two and 11 months of age, when milk is the primary food, and remains high until weaning. Its activity begins to decline until becoming very low in adulthood, a characteristic that varies between different ethnic groups. This programmed decline in lactase synthesis may cause abdominal and extraintestinal discomfort in many individuals that must be identified and treated correctly. On the other hand, under certain conditions, the proteins present in cow’s milk, such as casein, α-lactalbumin, and β-lactoglobulin act as antigens capable of triggering an immune-mediated response in children and are unrelated to intestinal lactase activity.16,17

2. The terms LNP, hypolactasia, lactose maldigestion, and LI describe different phenotypes with particular clinical implications.

Agreement percentage: 89.5% in complete agreement, 10.5% in partial agreement.

LIRDs make up a complex pathophysiologic complex that ranges from genetic predispositions to symptomatic clinical manifestations. A precise understanding of terminology is essential for the differential diagnosis and appropriate therapeutic management, given that terms are frequently used interchangeably in clinical practice, causing conceptual and diagnostic confusion18 (Table 2). The terms LNP, hypolactasia, lactose maldigestion, and LI describe distinct phenotypes with specific clinical implications that require differentiated diagnostic and therapeutic approaches.18 Each represents a specific level in the pathophysiologic cascade that ranges from the genetic basis to symptomatic clinical expression. The phenotypes associated with LIRDs are described below.

3. LNP is a genetically determined condition associated with reduced intestinal lactase expression.

Agreement percentage: 89.5% in complete agreement, 10.5% in partial agreement.

LNP is the normal ancestral phenotype in humans, characterized by a genetically determined downregulation of lactase activity after weaning.19,20 This phenotype is present in approximately 65–70 % of the adult world population and is associated with specific polymorphisms, such as the C/C-13910 in European populations.21,22 LNP makes up the original evolutionary state of the human species, reflecting the ancestral pattern of enzymatic expression that characterized the first Homo sapiens for millennia.23,24 From an evolutionary perspective, LNP is the “normal” or “wild-type” condition, whereas lactase persistence is a relatively recent evolutionary adaptation that emerged as a response to specific selective pressures related to animal domestication and dairy product consumption in adulthood.25,26 LPN’s underlying molecular mechanism involves the transcriptional regulation of the LCT gene (lactase-phlorizin hydrolase) located on chromosome 2q21. In individuals with LNP, lactase expression dramatically declines after weaning, reaching approximately 5−10% of the levels observed during infancy.27

4. Hypolactasia is the decrease in lactase enzymatic activity to a level that is insufficient for adequately hydrolyzing lactose into glucose and galactose, thereby impeding its absorption. It may be congenital, primary (genetically determined), or secondary.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement.

Hypolactasia is defined as the specific enzyme deficiency of LCT in the villi of the small bowel, with a lactase/sucrase index <0.3. It is the phenotypic expression of the most common enzyme deficiency in humans worldwide.28 This enzyme is responsible for hydrolyzing lactose into its constituent monosaccharides: glucose and galactose. The classification of hypolactasia is based on its etiology and time of appearance, distinguishing three main forms with specific pathophysiologic, diagnostic, and therapeutic characteristics:

Congenital hypolactasia: Congenital hypolactasia (more properly called alactasia) is a rare form in which there is an absence of lactase from birth that persists throughout life and is due to an inborn error of metabolism that cannot be reversed. It is caused by a genetic alteration, and its diagnosis is based on the selective, permanent deficiency of lactase activity, with normal intestinal mucosal histology. The incidence of alactasia is estimated at below 1:60,000 live births in Finnish populations.29 It is an autosomal recessive disease caused by mutations in the coding region of the LCT gene. It includes the Y1390X mutation, known as “Finn(Major)”, which accounts for up to 84% of cases in Finnish patients.8 Other pathogenic mutations have also been described, including deletions, point mutations, and frameshift mutations that cause premature truncations of the protein or critical amino acid substitutions, reflecting the existence of multiple genetic alterations in different populations.30 Clinically, patients present with severe, profuse watery diarrhea from the first days of life after the ingestion of breast milk or formulas with lactose.7,31 Symptom intensity impedes natural breastfeeding, making lactose-free formulas indispensable for preventing severe complications. If treatment is not adequate, the disease rapidly leads to dehydration, electrolyte imbalance, and failure to thrive.

Primary hypolactasia (genetically regulated): The most common phenotype of lactase deficiency in humans, primary hypolactasia affects approximately 65–70% of the global adult population.7,32 Also known as LNP (see the Phenotype section), the condition constitutes a genetically predetermined physiologic characteristic of autosomal recessive inheritance that is manifested by transcriptional downregulation of the LCT gene expression after weaning. In affected individuals, enzyme activity is progressively reduced until reaching only 5−10% of the maximum activity observed during infancy,17,18,33 with variations in age at onset and rate of enzymatic decline according to ethnicity. In molecular terms, LNP is strongly associated with the –13910 C>T (rs4988235) regulatory polymorphism, located on intron 13 of the MCM6 gene, which plays a key role in LCT transcription. Thus, individuals homozygous for C/C-13910 present with hypolactasia, whereas lactase persistence is seen in carriers of at least one T allele. Different mechanisms proposed for explaining reduced enzymatic activity include a decrease in lactase synthesis at the transcriptional level, post-translational modifications that reduce enzyme activity, and a greater susceptibility of the enzyme to proteolytic degradation during the post-weaning transition.34,35

Secondary hypolactasia (acquired): An acquired form of lactase deficiency, secondary hypolactasia is characterized by a transient or permanent decrease in enzymatic activity due to mucosal injury of the small bowel. Unlike primary hypolactasia, it is distinguished by its reversible potential, once the underlying disease is treated. The degree of enzymatic deficiency varies, in relation to the extent and severity of epithelial injury, and in many cases may coexist with the loss of other disaccharides, such as sucrase and maltase, especially in diseases that diffusely affect the brush border. The most common causes include infectious enteritis (rotavirus, norovirus, Giardia lamblia, and tropical enteropathy, among others), celiac disease, inflammatory bowel disease, medications (nonsteroidal anti-inflammatory drugs, olmesartan), radiation enteritis, and severe malnutrition. Clinically, the diagnosis is based on a history compatible with previous or concomitant intestinal disease, together with histologic evidence of villous atrophy or structural alterations of the intestinal villi. Likewise, functional tests may show improvement in lactose digestion after the mucosal injury is resolved, with recovery times ranging from weeks to months, depending on etiology and initial severity. The evaluation of the activity of other intestinal enzymes is useful for differentiating multiple deficiencies associated with the underlying disease.

5. LI occurs when lactose maldigestion causes symptoms, such as abdominal distension, abdominal pain, flatulence, diarrhea, and in some cases, nausea.

Agreement percentage: 94.7% complete agreement, 5.3% partial agreement.

Lactose maldigestion refers to the functional inability to hydrolyze a given amount of lactose in the small bowel, which may be objectively evaluated through diagnostic tests, such as the hydrogen (H2) breath test (see the Diagnosis section).36,37 This concept describes a physiologic process that does not necessarily translate into clinical symptoms, given that factors such as individual digestion thresholds, colonic adaptation capacity, and the gut microbiota, may modulate tolerance to different lactose doses. In contrast, LI is defined as the set of clinical manifestations that appear after lactose ingestion in subjects with documented lactose maldigestion.38,39 According to the 2010 National Health Institutes consensus, the diagnosis of LI requires symptom demonstration in a double-blind, placebo-controlled lactose challenge in an individual with confirmed deficient lactose digestion.40 Clinical manifestations include characteristic gastrointestinal symptoms of abdominal pain, bloating, flatulence, borborygmi, and/or diarrhea, which are due to colonic fermentation of undigested lactose by microorganisms in the gut microbiota and increased intraluminal osmotic presuure.41 In addition, some patients refer to extraintestinal symptoms, such as headache, dizziness, fatigue, muscle pain, and even palpitations or arrythmias, which have been described in clinical studies, albeit their pathophysiologic relation is unclear.39 Symptom intensity is dependent on multiple factors, including the quantity of lactose ingested, gastric emptying time, composition and fermentative capacity of the colonic microbiome, and functional comorbidities, such as irritable bowel syndrome (IBS) and individual visceral sensitivity, which explains the heterogeneity in the clinical presentation of LI.

Self-perceived LI refers to symptoms attributed to dairy product consumption, without having confirmed lactose maldigestion through standardized diagnostic tests.

Agreement percentage: 89.5% complete agreement, 10.5% partial agreement.

This condition is clinically relevant because its prevalence tends to be higher than that of confirmed intolerance, suggesting that a considerable number of persons unnecessarily eliminate or restrict dairy products from their diet. The discrepancy may be due to multiple factors: the placebo/nocebo effect, coexistence of functional gastrointestinal disorders, such as IBS and visceral hypersensitivity, and the influence of psychologic and sociocultural factors involved in symptom perception. For example, patients with IBS report self-perceived LI 3.5 times more than healthy controls (odds ratio [OR] = 3.4), regardless of the presence of deficient lactose digestion objectively documented through H2 breath testing.42,43 Said discrepancy is explained by the presence of visceral hypersensitivity, a fundamental characteristic of IBS that amplifies the gastrointestinal symptom perception of stimuli that would normally be sub-threshold.44 Barostat studies show that lactulose administration significantly reduces discomfort thresholds in subjects with LI but not in those with asymptomatic deficient lactose digestion, establishing a direct correlation between symptom severity and reduced visceral pain thresholds.45 Self-perceived LI, unlike documented intolerance, lacks a direct correlation with lactose maldigestion, highlighting the importance of utilizing objective criteria to prevent erroneous diagnoses and potential nutritional consequences of unnecessary dairy product restriction, such as calcium and vitamin D deficiencies.

6. The term “lactose sensitivity” is proposed for grouping individuals who develop symptoms during a breath test with 25 g of lactose, despite having normal lactose digestion.

Agreement percentage: 94.4% complete agreement, 5.6% partial agreement.

The concept of “lactose sensitivity” without lactose maldigestion seeks to encompass patients who, during a breath test with a pharmacologic dose of lactose, show normal lactose digestion, but develop gastrointestinal symptoms. In a cohort of 1,230 patients with chronic gastrointestinal symptoms, 590 underwent lactose breath testing. Fifty-two (9%) of them presented with lactose “hypersensitivity”, defined as the appearance of significant symptoms with no concomitant increase in H2 or methane (CH4) levels.46 Said phenomenon, described in both adult and pediatric populations, reflects the influence of factors such as visceral hypersensitivity, intestinal motility disorders, altered colonic microbiota, and possibly the nocebo effect. That finding underlines the fact that not all symptoms related to lactose are explained by malabsorption; in certain individuals, lactose may behave as a highly fermentable sugar or FODMAP (acronym for fermentable oligosaccharide disaccharides, monosaccharides, and polyols), triggering symptoms due to their fermentative and osmotic effects in the presence of adequate digestion. Recognizing this entity is especially relevant in pediatrics, where unnecessary dietary restrictions may have important nutritional consequences. Psychologic factors play a cardinal modulatory role, given that patients with lactose sensitivity present with significantly higher scores on depression and anxiety scales, compared with patients who have asymptomatic deficient lactose digestion.47,48 This complex interaction explains why up to 30% of patients with self-perceived LI have normal lactose digestion and normal sensitivity on objective tests, suggesting that “functional LI” is a manifestation of IBS, more than a true enzyme deficiency.49,50 In a clinical context, said overlap requires a thorough diagnostic evaluation that includes objective tests for lactose maldigestion, considering IBS diagnostic criteria, given that the therapeutic management of the two conditions differs substantially. Dietary lactose restriction is only effective in cases of documented lactose maldigestion, whereas patients with IBS benefit more from therapeutic approaches targeting visceral hypersensitivity and underlying psychosocial factors.51

7. LNP is a common condition worldwide, with notable ethnic and regional variations.

Agreement percentage: 100% complete agreement.

The geographic distribution of LNP reflects patterns shaped by human evolutionary history and local selective pressures. In European populations, the –13910C>T (rs4988235) polymorphism is the principal genetic marker, with frequencies of the C allele (associated with LNP) that vary from under 10% in Scandinavian populations to more than 80% in southern Europe.52,53 There is greater genetic diversity in African populations, with multiple polymorphisms associated with lactase persistence, including −13915T>G, in nomadic Arab and East African populations, and –13907C>G, in Sudanese populations, indicating that LNP is determined by different genetic variants depending on population origin.54,55

In Latin America, including Mexico, the frequency of LNP reflects the genetic composition of mestizo populations. Studies on Chilean populations have shown that 56.9% of Hispanic individuals present with the CC genotype (LNP), whereas in Amerindian populations said frequency reaches 88.3%.56 This distribution suggests that the majority of the Latin American population has a genetic predisposition to LNP, even though the phenotypic expression may be modulated by environmental and adaptive factors. In the Mexican population, the −13910:C>T (rs4988235) polymorphism associated with lactase persistence has been identified.57 It has a frequency of 20% in rural areas of Mexico. Variability in lactase persistence frequency related to ethnicity has also been reported, with 30% frequency in Mexicans from rural areas. LNP also has fascinating evolutionary implications, from the perspective of gene/culture coevolution. Milk-producing animal domestication (cattle, goats, sheep) approximately 10,000 years ago created a new selective pressure that favored mutations enabling lactose digestion in adults. However, said selective pressure was not globally uniform, explaining why LNP remains the predominant phenotype in many populations that historically did not depend on pastoralism or the consumption of dairy products.58,59

Hypolactasia and LI are common conditions in Mexico. Their estimated prevalence varies, depending on diagnostic methodology and the population studied.

Agreement percentage: 100% complete agreement.

Despite the fact that there are few studies conducted in Mexico, LNP and LI are highly prevalent conditions in our country, with an epidemiologic distribution that reflects its geographic and genetic diversity. The most comprehensive Mexican epidemiologic studies, conducted using prospective, randomized, double-blind, and cross-over designs in 960 individuals from 1 to 99 years of age, show marked regional variability in the prevalence of lactose maldigestion: 9% in the northern region, 30% in the central region, and 22% in the southeastern region (p < 0.01), reflecting the differences in the genetic composition of populations resulting from historic patterns of migration and genetic admixture.9,60 Prevalence also has a characteristic age pattern, progressively increasing from 4.5% in children under three years of age, 13.6% in the 3–5.9-year age group, 20.8% in children 6–12.9 years of age, and 21.8% in adolescents 13–17.9 years of age, until reaching, 32.9% in the adult population, following the expected kinetics of physiologic decline in lactase activity, after weaning.10,12 In the Mexican adult population, primary hypolactasia affects 30% of individuals, when physiologic doses equivalent to one glass of milk (12−18 g of lactose) are consumed, whereas symptomatic clinical intolerance presents only in fewer than 15% of adults at the same doses, revealing the important discrepancy between enzyme activity and clinical intolerance.9,11,12,58,59 The diagnostic methods employed in those studies principally include the H2 breath test with physiologic doses of milk (240 mL for children, 360 mL for adults), instead of pharmacologic lactose loads, providing more representative data on real-world consumption conditions.61,62 Recent studies on Mexican adolescents (15–18 years of age) reported a prevalence of LI of barely 0.5% (95% CI 0.2−0.8%), considerably lower than other milk-related disorders, suggesting that the diagnostic methodology and definition of intolerance significantly influence prevalence estimates.63 On the other hand, there were no significant differences between rural and urban populations regarding the prevalence of lactose maldigestion, even though milk consumption was significantly higher in urban areas. Deficient lactose digestion also only marginally affected dairy product consumption, indicating that factors unrelated to digestive capacity largely determine dairy product consumption patterns in the Mexican population.9,10,58–60 The need for more recent epidemiologic data utilizing current definitions and appropriate diagnostic tests for establishing the true prevalence of LIRDs in Mexico should be emphasized.

8. Clinical diagnosis based solely on the presence of symptoms after lactose ingestion is not a reliable method for diagnosing LI.

Agreement percentage: 88.9% complete agreement, 11.1% partial agreement.

Quality of evidence: A

Strength of the recommendation: Strong against the statement.

The correlation between self-reported symptoms and objective findings of deficient lactose absorption tests is consistently low, indicating a complex interaction of physiologic and psychologic factors. The sensitivity and specificity of symptoms, such as abdominal pain, bloating, flatulence, and diarrhea are very limited, with the former ranging from 0 and 90% and the latter between 18 and 96%, making the self-reporting of intolerance an unreliable indicator (sensitivity: 30–71%; specificity: 25–87%).7,16,26 A marked placebo effect has also been described: studies show that up to 59% of patients with lactose maldigestion report symptoms during an open milk challenge, but there are no significant differences when compared with placebo. In addition, patients with severe self-reported intolerance do not always have positive results on lactose maldigestion tests.40 Nevertheless, even though the self-perception of lactose consumption-related symptoms tends to overestimate intolerance, it can help identify patients who should undergo diagnostic testing to rule out lactose maldigestion.64

Performing diagnostic tests for correctly classifying individuals with LIRDs is recommended.

Agreement percentage: 94.7% complete agreement, 5.3% partial agreement; Quality of evidence: A; Strength of the recommendation: Strong for the statement

As has been noted, the presence of gastrointestinal symptoms, such as abdominal distension, diarrhea, and abdominal pain, are part of the clinical spectrum of LIRDs, but they are not exclusive. There are at least five validated tests (Table 3) with higher sensitivity and specificity than symptoms alone, and they enable the objective and correct classification of patients with LI. Therefore, diagnosing LI based solely on clinical data is not recommended; the clinical data should be complemented with other tests for an accurate assessment.

Genetic testing can identify specific polymorphisms (such as C-13910T and G-22018) that are useful for epidemiologic studies. However, they do not diagnose LI because the presence of said polymorphisms does not always correlate with symptoms.

Agreement percentage: 100% complete agreement; Quality of evidence: A; Strength of the recommendation: Strong for the statement.

The lactase-encoding gene is found on chromosome 2 (2q21) and has 17 exons. At present, a total of twenty-three gene variants associated with lactase persistence have been described in different human populations.58 Said variants are mainly found in the regulatory region of the MCM6 gene, which acts as an enhancer of LCT gene expression. The polymorphisms in the MCM6 gene can be measured through genetic tests, such as real-time PCR or DNA sequencing from saliva or peripheral blood samples.7

The key polymorphisms include:

• 1

  C/T-13910 (LCT-13910C/T): This variant is one of the most widely studied and is associated with adult-type lactase persistence. The C/T-13910 polymorphism has C/C variants associated with nonpersistence of enzyme activity and C/T or T/T variants associated with persistence.65 Individuals homozygous for the C allele (LCT-13'910:C/C) are less likely to express lactase, which leads to LNP, and consequently, lactose maldigestion. The T allele is commonly found in populations with a high frequency of lactase persistence, particularly in northern Europe.

• 2

  G/A-22018 (LCT-22018G/A) is another polymorphism that has been related to lactase persistence in some populations.58

• 3

  There are other polymorphisms in African and Middle Eastern populations and the mechanisms for the intolerance phenotype involve reduced mRNA production or altered gene transcription. Even though genetic tests theoretically enable the accurate identification of genetic predisposition and can guide dietary treatment, thus preventing unnecessary restrictions and improving patient quality of life, one of their limitations is the variable correlation between the genotype, actual lactose-related symptoms, and other diagnostic tests. For example, a 55% correlation has been described in the pediatric population, whereas it can reach 86% in the adult population. Their greatest usefulness is undoubtedly in epidemiologic studies.22,66,67

9. The measurement of lactase activity in duodenal tissue has a diagnostic utility similar to that of the H2breath test.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement.

Quality of evidence: B

Strength of the recommendation: Weak for the statement.

Lactase activity measurement in duodenal tissue requires at least two biopsy samples taken from the second or third portion of the duodenum during upper gastrointestinal endoscopy.68 Lactase activity can be measured by the in vitro Dahlqvist method, which determines enzyme activity through colorimetry, using the Tris-glucose oxidase (TGO) reagent.69 Results are expressed in lactase units (μM/min/g of protein). The rapid lactase test (Biohit®) is a colorimetric assay, in which the duodenal biopsy sample is placed on a test plate, and different reagents are added to it.70 A change in color at 20 min determines the presence or absence of lactase. These tests may be justified in patients undergoing endoscopy due to gastrointestinal symptoms. A recent study on 498 patients with gastrointestinal symptoms evaluated through the Dahlqvist technique found a 28% prevalence of lactase deficiency.71 Studies that have compared lactase activity measurement in duodenal tissue with breath testing have shown 83% agreement and both methods predict response to a lactose-free diet, in 98% and 81% of cases, respectively.72 False negatives may occur if biopsies are taken from the first portion of the duodenum, or due to the patchy distribution of intestinal hypolactasia. Importantly, duodenal lactase activity measurement is invasive, expensive, and its availability in Mexico is limited.

10. The lactose tolerance test (blood glucose after an oral lactose load) is a minimally invasive test through which lactose maldigestion can be diagnosed. Its agreement with other tests is variable.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement.

Quality of evidence: B

Strength of the recommendation: Strong for the statement.

The lactose tolerance test, or blood glucose test after a lactose load, measures serum glucose before and after ingesting a drink containing lactose, and is an alternative to symptom-based diagnosis and breath testing.7,73 It is performed similarly to the oral glucose tolerance test, with measurements taken at 0, 30, 60, and 120 min after the oral administration of 50 g of lactose. It requires a fast of at least 12 h. In healthy individuals, an increase in serum glucose, compared with the baseline level, is expected. In patients with LI, glucose levels remain unchanged or increase by less than 20 mg/dL (1.1 mmol/dL) during the test and is considered positive for lactose maldigestion. This test evaluates symptoms and both LI and lactose maldigestion can be diagnosed. Studies on pediatric populations have compared breath tests with the blood glucose test after an oral lactose load, demonstrating 50% sensitivity, 94% specificity, a positive predictive value (PPV) of 87%, and a negative predictive value (NPV) of 89%, with significant association (p < 0.001) and moderate agreement (Phi coefficient = 0.493, p < 0.001) for the diagnosis of lactose maldigestion.74 A study evaluated the diagnostic accuracy of different tests for detecting LNP. A breath test, blood glucose test after a lactose load, and urinary galactose/creatinine measurement were performed, at separate cross-over visits, on 40 women, 14 of whom were diagnosed with LNP through genetic testing (C/C13910 and G/G22018).73 The three tests discriminated well between individuals with lactase persistence and those with LNP, with an area under the curve of 1.00 (breath test), 0.75 (blood glucose test), and 0.73 (test in urine), but <0.70 after the administration of milk (blood glucose test and test in urine). The greatest limitations of the lactose tolerance test (blood glucose test) are the discomfort associated with taking the blood sample and the finger-prick blood sampling at various intervals. It also requires an integral gastrointestinal tract. There may be false negatives in cases of gastrointestinal anatomy-modifying surgery (e.g., gastrectomy, gastric bypass surgery), deficient intestinal absorption syndromes, glucose metabolism disorders, or the use of medications that modify gastrointestinal motility, as well as antibiotic or gastric antisecretory agent use.

11. The serum gaxilose test after an oral load reliably provides an indirect estimate of lactase activity. However, there may be false positives due to small intestinal bacterial overgrowth or accelerated bowel transit.

Agreement percentage: 100% complete agreement.

Quality of evidence: B

Strength of the recommendation: Strong for the statement.

The protocol of the serum gaxilose test is similar to that of the lactose tolerance test, except that it employs the oral administration of gaxilose, a variety of the D-xylose test (4-galactosyl-xylose [4-O-β-D galactopyranosyl-D-xylose]), which enables the detection of D-xylose in serum or galactosidase in urine after being hydrolyzed by lactase (see further ahead).7,63 Various studies have evaluated its clinical utility and diagnostic yield. One study compared the diagnostic accuracy of three tests (urinary and serum measurement after gaxilose administration, the lactose tolerance test, and clinical criteria through a symptom questionnaire for the diagnosis of primary hypolactasia, using the C/T13910 polymorphism as the reference standard, in 70 women (36.8% with primary hypolactasia).75 The variables with the highest level of agreement (k > 0.60) were the presence of diarrhea and the symptom score, as well as the oral tolerance test, with >80% sensitivity and specificity and an area under the curve >0.82. The gaxilose test had lower scores, and in the multivariate analysis, the post-load symptom score was associated with the genetic test. Even though the gaxilose test measures lactase activity along the entire intestine, and theoretically would be superior, there are contradictory results when comparing its sensitivity and specificity with other tests. A study sponsored by the company that makes it, reported superior diagnostic accuracy (sensitivity, specificity, predictive values >90%), compared with the H2 breath test,69 and the oral tolerance test (85%), with an area under the curve >0.9 (p < 0.007), whereas Domínguez et al.,75 who used genetic testing as the reference, did not confirm those findings.31 A third study reported that the gaxilose test was not inferior to the breath test.76 The limitations of the gaxilose test are the same as those described for the glucose tolerance test, only with the added factor that there may be false positives in patients with small intestinal bacterial overgrowth or accelerated bowel transit.7

12. Performing a breath test after the administration of 25 g of lactose is recommended because it helps classify the phenotypes of LIRDs.

Agreement percentage: 100% complete agreement.

Quality of evidence: A

Strength of the recommendation: Strong for the statement.

The breath test measures H2 and CH4 excretion after the administration of 25 g of lactose.7,34,35 It is a noninvasive test in which the patient fasts for at least 8 h, follows a low-fiber diet the night before, has not taken antibiotics in two weeks, and has not smoked or done intense exercise before the test. A baseline breath sample is obtained before lactose administration, and after the ingestion of 25 g of lactose dissolved in 200 mL of water, air samples are taken every 15 min for 3 h. The quantity of H2 and CH4 is expressed in parts per million, measured by gas chromatography. According to different consensuses, the test is considered positive for lactose maldigestion if there is an increase in H2 ≥ 20 ppm and/or of CH4 ≥ 10 ppm. To diagnose LI in each exhaled breath sample, symptom questionnaires are applied, thus identifying the different phenotypes (Table 2). Validation studies show that the breath test has 95% sensitivity and 67% specificity when evaluated for 3 h, with a cutoff point ≥20 ppm above the baseline value for H2 increase, albeit those parameters vary significantly, according to protocol duration, drastically reducing sensitivity to 37% when limited to 1 h.77,78 However, other studies report wider margins of diagnostic yield. Sensitivity ranges from 56 to 95% and specificity from 67 to 93% when compared with reference methods, such as duodenal biopsy, reflecting the heterogeneity in study methodologies and populations.79,80 Despite its wide clinical acceptance, the breath test cannot be considered a true gold standard due to its significant inherent limitations, including the approximate 10–15 % of individuals who are H2 “non-producers”, the need to consider CH4 production in 16% of individuals with normal lactose digestion, and to a lesser degree, hydrogen sulfide (H₂S) production. There are also confounding factors, such as small intestinal bacterial overgrowth, medications, dietary fiber, and variations in the colonic microbiota.81–83 Upon comparing the breath test with lactase activity in intestinal biopsy, the former shows 74% sensitivity and 89% specificity, with a 9.2% discordance rate.84,85 The test is available in Mexico, but its accessibility is limited, with only a few centers having the necessary equipment. Its cost varies, according to the different public and private centers. Importantly, the test takes 3−4 h, and during the process, lactose ingestion may cause bothersome gastrointestinal symptoms (abdominal pain, bloating, diarrhea, gases).

13. Following a lactose load, validated questionnaires are useful for evaluating gastrointestinal symptom intensity.

Agreement percentage: 100% complete agreement.

Quality of evidence: B

Strength of the recommendation: Weak for the statement.

Fifty-five percent of individuals who have self-perceived LI are estimated to present with lactose maldigestion after an oral 20 g lactose load.86 The probability of a positive breath test with lactose has been calculated to be four-times higher, if there are also symptoms suggestive of LI.87 Furthermore, persons with genetically identified lactose deficiency have twice the risk of increased H2 in the test by only presenting with abdominal distension, 12-times the risk if they present with borborygmus, and seven-times the risk if there is visceral hypersensitivity, suggesting that the symptoms not only reflect central and psychologic factors (such as hypervigilance), but also peripheral dysfunction related to the innate immune intestinal system or the effects of fermentation products and intestinal sensorimotor function. Therefore, questionnaires have been developed that evaluate the intensity and prediction value of different symptoms. A study included 292 patients who completed a questionnaire on five symptoms (diarrhea, pain, nausea, inflammation, and flatulence) graded on a 10 cm visual analogue scale after having undergone a breath test with 50 g of lactose. The patients were separated into lactose digestors and non-digestors, according to the H2 breath test results. The total score of the questionnaire was significantly higher in the patients with lactose maldigestion (17.5 vs 3.0; p < 0.01). The cutoff point that better identified deficient digestion was 6.5 (sensitivity 0.75, specificity 0.67). Relevantly, the study showed that the diagnostic yield of the questionnaire was better when applied at home than directly after the breath test and is proposed as an alternative for screening patients who require additional studies to confirm the lactose maldigestion diagnosis.86 Hammer et al.87 developed the Adult Carbohydrate Perception Questionnaire (aCPQ), a questionnaire in German for evaluating gastrointestinal symptoms on a 100 mm visual analogue scale after carbohydrate ingestion. The questionnaire had sensitivity of 0.66 and specificity of 0.58, for identifying deficient carbohydrate digestion. With a 43% prevalence of deficient digestion, the PPV was 0.54 and the NPV was 0.69 in the original group, whereas sensitivity was 0.68, specificity was 0.60, and the frequency of deficient digestion was 37%, with a PPV of 0.5 and a NPV of 0.76, in the external validation group.88 The Casellas questionnaire is available in Spanish, and the Hammer questionnaire is in the process of translation and adaptation to Spanish. A disadvantage of the validated questionnaires is that they are based on the subjective perception of each patient, which introduces bias and interindividual variability. The reported symptoms also lack specificity, given that they can be present in other gastrointestinal disorders, and their correlation with objective diagnostic tests tends to be limited, reducing their usefulness as a standalone diagnostic method.

14. In patients with self-perceived LI, the urinary gaxilose test has shown good agreement with lactase activity.

Agreement percentage: 100% complete agreement.

Quality of evidence: B

Strength of the recommendation: Weak for the statement.

The gaxilose test indirectly measures intestinal lactase activity. It is based on the quantification of urinary xylose after gaxilose administration.89,90 The test is validated and easy to perform. It requires oral gaxilose administration and urine collection over 5 h. Urinary xylose is quantified using gas chromatography equipment. A portable device has recently been developed that detects gaxilose concentrations in urine through reagent strips. Test results indicate hypolactasia or normal lactasia.31,91 The manufacturer’s recommended cutoff point is 19.18 mg in a total 5-h volume. Values below that figure are indicative of hypolactasia, whereas values above it indicate normal lactasia.91 Importantly, gastrointestinal symptoms cannot be evaluated while carrying out the test because a low quantity of gaxilose is administered (0.45 g [LacTest®] diluted in 200 mL), but it has the advantage of being tolerated by anyone who can fast for more than 10 h, given that fasting is required before the test, as well as during the 5-h urine collection. Up to 700 mL of plain water may be ingested during that time. In an open, multicenter phase IIb-III study, the results of intestinal biopsies, genetic markers (C/T 13910 and G/A 22018 polymorphisms), breath testing with lactose (50 g in 400 mL), blood glucose test after a lactose challenge, and urinary and serum gaxilose tests were evaluated in 222 patients with suspected LI. Compared with the intestinal biopsies, the 5-h test in urine had 93.5% sensitivity, 91.8% specificity, and a positive likelihood ratio of 11.3; compared with the genetic test, the 5 -h urine test had 68.5% sensitivity, 92.2% specificity, and a likelihood ratio of 8.8. Compared with intestinal biopsy, the breath test had 73.2% sensitivity, 85.6 specificity, and a positive likelihood ratio of 5.1, whereas the blood glucose test had 69.4% sensitivity, 78.4% specificity, and a positive likelihood ratio of 3.2 after the lactose challenge.31 An additional advantage of the 5-h urine test is its potential capacity for discriminating primary hypolactasia from secondary hypolactasia. A recent study on patients with IBS and bacterial overgrowth, who presented with low levels of xylose in urine after the 0.45 g LacTEST® (hypolactasia at the beginning of the study), showed a significant increase in xylose levels and symptom improvement, four weeks after receiving a two-week treatment for bacterial overgrowth.92 Those data suggest that even in a short period of time, changes may be observed in intestinal lactase activity that are correlated with clinical improvement. The 5-h urine test is in the process of being introduced in Mexico and multiple studies on it are showing promising results. Its cost is lower than that of the other tests and its practicality is adequate. However, it should not be used in patients with severe kidney disease, portal hypertension, myxedema, diabetes mellitus, or a history of total gastrectomy and/or vagotomy.

15. Personalized dietary treatment is required in cases of LI. The correct approach includes a low-dairy or dairy-free diet.

Agreement percentage: 89.5% complete agreement, 11.5% partial agreement.

Quality of evidence: Moderate; Strength of the recommendation: Strong for the intervention.

The treatment of LI primarily consists of reducing or eliminating the quantity of dietary lactose and preventing long-term malnutrition. It should also be in accordance with each patient’s tolerance, and thus be individualized.7 Most patients with a LIRD may come to tolerate 5 g of lactose as a single daily dose,93 with an increase in the tolerance threshold if it is distributed throughout the day together with other nutrients that delay gastric emptying and bowel transit,94 giving lactose more time to be hydrolyzed and its components absorbed.95 Variations in the quantity of lactose that can be tolerated in individuals with LI range from 5 to 15 g. Persons with LI do not need to completely eliminate dairy products from their diet.96 Whey is a byproduct of cheese production and contains 80% lactose and 20% proteins. It is dried and the powder is often added to numerous dairy and non-dairy products, which is why lactose can be found in certain breads, baked goods, ready-to-eat cereals, instant soups, candies, cookies, salad dressings, sausages, sauces, beverage mixes, and margarine. This additive is commonly referred to as “hidden lactose”. It is important to pay attention to the list of ingredients of processed foods, to not exceed the individual lactose tolerance threshold. Terms indicating the presence of lactose include curd, whey, milk, dairy byproducts, dried milk solids, and powdered milk.97Table 4 lists the most common dairy products and their lactose content.

16. When LI is transient, the temporary exclusion of milk and lactose-containing products is recommended, followed by gradual reintroduction.

Agreement percentage: 89.5% complete agreement, 11.5% partial agreement.

Quality of evidence: Weak.

Strength of the recommendation: Strong for the intervention.

Treatment of transient LI (such as after acute infectious diarrhea) mainly consists of reducing and/or eliminating dietary lactose until symptoms disappear. Lactose-free products or lactase ingestion are other options. The gradual reintroduction of 30−60 mL of milk daily is recommended and it should be progressively increased until reaching 250 mL, while evaluating the tolerance of each patient.98

17. Some individuals with LI may tolerate foods with a low lactose content, such as yogurt, kefir, and aged cheeses, when consumed throughout the day.

Agreement percentage: 94.7% complete agreement, 5.3% partial agreement.

Quality of evidence: Weak.

Strength of the recommendation: Weak for the intervention.

There is generally less lactose in fermented dairy products than in the equivalent quantity of milk. In turn, products, such as yogurt, contain lactic bacteria that slightly reduce lactose content. Lactose-free dairy products are based on the industrial addition of lactase to hydrolyze the lactose and obtain glucose and galactose. Milk is ultrafiltered through a membrane to eliminate its lactose content, obtaining lactose-free milk,100 making it possible for individuals with LI to enjoy the taste of dairy products, without experiencing the intestinal symptoms that occur after lactose ingestion. Lactose content is generally required to be under 1 g/100 g in low-lactose products and under 10 mg/100 g in lactose-free products. Lactose-free dairy products can provide the essential nutrients normally present in conventional dairy products, such as calcium and vitamins.102

18. Individuals presenting with LI and greater calcium requirements, such as adolescents, pregnant or breastfeeding women, perimenopausal women, and older adults, may require calcium supplementation, along with considering alternative dietary sources.

Agreement percentage: 89.5% complete agreement, 11.5% partial agreement.

Quality of evidence: Moderate.

Strength of the recommendation: Weak for the intervention.

Calcium requirements are the same for men and women during the first 50 years of life (one to three years of age: 700 mg Ca/day; four to eight years of age and 19−50 years of age: 1,000 mg Ca/day), with highest recommended intake during adolescence, when there is maximum bone growth (nine to 18 years of age: 1,300 mg Ca/day). These values begin to change with the onset of menopause: the recommended calcium intake for women increases to 1,200 mg Ca/day, and values are equal to those of men when both sexes reach 70 years of age, with a recommended intake of 1,200 mg Ca/day, to prevent the development of osteoporosis103 (Table 5). Dairy product restriction in LI leads to reduced calcium intake, and so the consumption of other calcium-rich foods, such as tortillas, dried small fish (charales), sardines, broccoli, leafy green vegetables, fish, and dried fruit should be increased to prevent nutritional deficiencies resulting from limiting one of the main sources of calcium. Lactose-free food intake is another option that may be considered (Table 6).

19. Exogenous enzyme (lactase) use is recommended in patients with LI, to reduce the gastrointestinal symptoms associated with lactose consumption.

Agreement percentage: 100% complete agreement.

Quality of evidence: Low.

Strength of the recommendation: Weak for the intervention.

The use of exogenous enzymes is a treatment option in patients with LI who wish to continue consuming milk and dairy products. Some studies have shown that said enzyme consumption is associated with improved gastrointestinal symptoms and reduced H2 emission in breath tests with the administration of 1,500 U/day of β-galactosidase in 40% of patients. In the remaining 60%, there was only slight improvement, despite the reduced H2 excretion,104 thus more studies are needed regarding exogenous enzyme efficacy. Lactase can be obtained from yeasts, such as Kluyveromyces lactis, or from fungi, such as Aspergillus oryzae and Aspergillus niger.105 Nevertheless, products obtained from those microorganisms have been reported to cause allergic reactions.106 Lactase should be administered approximately 5−30 min before ingesting foods containing lactose.107 The enzymes are found in numerous pharmaceutical presentations, including tablets, capsules, orodispersible films, liquid solutions, and gastro-resistant formulations, facilitating their adaptation to distinct clinical settings.108,109 Clinical efficacy is well documented: lactase digestion improvement (reduction in exhaled H2 from 100% to 48.9%), symptom improvement (51.1%–13.3% in symptomatic patients), increased dairy product tolerance (consumption capacity of up to 400 mL of milk with no symptoms), and a positive impact on patient quality of life.110,111 Exogenous lactase has an excellent safety profile, with decades of documented clinical use, and is classified as "Generally Recognized as Safe" (GRAS) by the US Food and drug Administration (FDA), with a similar status in international regulations. Fortunately, these enzymes are available in Mexico. One of the most common and practical presentations in tablets for adults with LI is β-galactosidase because it provides rapid dosing adjusted to the lactose content in foods. The recommended dose varies from 3,000 to 9,000 Food Chemical Codex (FCC) units per meal and should be taken before or at the same time as consuming the dairy product.

.

20. There is insufficient evidence on the use of probiotics for improving LI symptoms.

.

Agreement percentage: 100% complete agreement.

Quality of evidence: Weak.

Strength of the recommendation: Weak for the intervention.

.

Probiotics are defined by the World Health Organization (WHO) as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. The recent use of specific probiotic strains, especially those capable of expressing galactosidase enzyme activity, has been proposed as a treatment alternative in LI, or as adjunctive treatment, given their ability to modulate the microbiota and promote lactose digestion.112 Probiotics have also been described to secrete lactase outside their cell membranes, generating greater activity at the intestinal level. According to those reports, bile-sensitive probiotics may be utilized for transporting lactase or other active components of the gastrointestinal tract. In other words, the probiotics that arrive at the digestive system act as a source of β-galactosidase and increase overall hydrolytic capacity and colonic fermentation.113 Those benefits depend on the specificity of the probiotic strain used and the most widely studied strains are the Lactobacillus and Bifidobacterium genera. Besseling-van der Vaart et al.114 evaluated galactosidase enzyme activity in specific Bifidobacteria and Lactobacilli strains in vitro, finding greater activity in Lactobacillus acidophilus W22 and W70, Lactobacillus salivarius W24, Streptococcus thermophilus W69, and to a lesser degree, in Bifidobacterium lactis W52 and W51. The presence of lactase in probiotics is the main reason they can ferment dairy products, given that during the digestion process in the gastrointestinal tract, probiotics are lysed by the bile in the small bowel, releasing the enzymes capable of hydrolyzing lactose.115 In the most recent meta-analysis by Ahn et al.,116,117 conducted in 2023, they showed that probiotics improved symptoms of LI, specifically abdominal pain, diarrhea, and flatulence. In the meta-ANOVA test, abdominal pain and total symptoms decreased with single-strain probiotics. Lactobacillus acidophilus was used in three cases and Bifidobacterium sp. in six cases. In another study, Gingold-Belfer et al.118 used probiotic combinations of Limosilactobacillus reuteri, Lacticaseibacillus casei Shirota, Streptococcus thermophilus, and L. delbrueckii spp. bulgaricus, and also evaluated Lactobacillus plantarum and Lactobacillus rhamnosus. They found that the frequency of most of the symptoms, including bloating and flatulence, improved after treatment, compared with the baseline scores. In addition, 25% of individuals normalized their breath test. On the other hand, in only one study, in which Lactobacillus plantarum and Bifidobacterium animalis were administered, there were no significant differences in clinical manifestations. In another study, Bifidobacterium animalis subsp. lactis Bi-07119 was superior to placebo in two controlled clinical trials, in reducing the area under the curve in breath testing. However, during symptom evaluation, there were no significant changes between groups. In Mexico, the study by Cano-Contreras et al.120 evaluated a formula composed of three probiotic strains: Lactobacillus plantarum (CECT7484 and CECT7485) and Pediococcus acidilactici (CECT7483) that had previously been studied in patients with IBS, showing improved quality of life and anxiety scores. Cano-Contreras tested the formula on patients with LI through a randomized, placebo-controlled study that included 48 participants. The results showed a statistically significant reduction in the total symptom score (−5.11 vs −1.00; p < 0.001), abdominal pain (p = 0.045), and flatulence (p = 0.004), compared with placebo, as well as an adequate safety profile. Importantly, however, differences in lifestyle, geographic region, diet, and water consumption have been described to produce differences in probiotic therapy response, and so further studies are required. Likewise, the quantity of lactose ingested is an important factor in the appearance of malabsorption symptoms, as is the residual lactase activity of each individual, the colonic capacity of water absorption, and microbial composition, among other factors. Therefore, modulating the microbiome through probiotic strains with galactosidase activity could be an efficacious approach for treating patients with LI. Such treatment might improve tolerance to small amounts of lactose, with a prolonged effect, and eliminate the need to take medications right before each meal, resulting in important quality-of-life benefits for patients.94

21. Increasing lactose intake does not stimulate intestinal lactase production.

Agreement percentage: 94.7% complete agreement, 6.3% partial agreement.

Quality of evidence: High.

Strength of the recommendation: Strong against the intervention.

Studies on humans that have attempted to stimulate intestinal lactase production have been unsuccessful. Lactose administration does not induce intestinal lactase synthesis nor does suspending lactose consumption reduce its production.121 However, a diet that includes lactose may induce the growth of the intestinal bacteria that digest it (Lactobacillus and Bifidobacterium), resulting in better tolerance to the carbohydrate (colonic adaptation). Conversely, reducing lactose intake may decrease its tolerance, by reducing the beneficial microbiota.

22. The treatment of bacterial overgrowth in patients with IBS and lactose maldigestion may improve lactose tolerance.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement.

Quality of evidence: Low.

Strength of the recommendation: Weak for the intervention.

Bacterial overgrowth could reduce intestinal enzyme activity, including brush-border lactase.122 In a prospective pilot study on 25 patients with LI and bacterial overgrowth demonstrated by breath testing, administration of rifaximin improved lactase activity and reduced lactose maldigestion.92

LI in pediatrics is generally transient. Its treatment requires careful evaluation and accurate diagnosis of the underlying cause.

Agreement percentage: 94.7% complete agreement, 6.3% partial agreement; Quality of evidence: High; Strength of the recommendation: Strong for the intervention.

Pediatric patients with LI frequently have an underlying condition that causes transient lactase loss, such as infectious enteritis, and so dietary treatment should always be individualized.123 Treatment should focus on resolving the underlying cause (such as infections or enteropathies), and once resolved, lactose should be reincorporated into the diet to prevent nutritional deficiencies. The patient’s age group should also be taken into account when evaluating the underlying etiology. For example, in children under one year of age, conditions, such as cow’s milk protein allergy with secondary LI, should be suspected. Because cow’s milk protein allergy and LI may present with similar gastrointestinal symptoms, accurate diagnostic differentiation is essential for preventing excessive dietary restrictions or the unnecessary use of extensively hydrolyzed or amino acid-based formulas.124 In school-aged children and adolescents, a frequent cause of LI is infectious gastroenteritis, whether viral (rotavirus), bacterial, or parasitic. By treating the causative agent, and considering that the condition is usually self-limited, lactose restriction should be temporary. Lactose plays an essential role in the nutrition of infants and children. It promotes the development of a microbiota rich in bifidobacteria and supplies galactose, which is fundamental for growth, the formation of hepatic glycogen, and the synthesis of essential macromolecules, such as the galactocerebrosides, which are critical for brain development.125 Lactose-free milk or dairy formulas use maltodextrins, which have a high glycemic index, as lactose substitutes.

23. The treatment of LI in pediatrics should be focused on a moderate decrease in dairy product intake, allowing the consumption of fermented products, such as yogurt and aged cheeses, which are better tolerated and contribute to adequate nutrition.

Agreement percentage: 89.5% complete agreement, 10.5% partial agreement.

Quality of evidence: Moderate.

Strength of the recommendation: Strong for the intervention.

In school-aged children and adolescents with LI, a personalized diet is recommended that includes low-lactose or fermented dairy products, such as yogurt, to ensure an adequate supply of calcium and vitamin D. In a cohort of more than 2,000 Swiss children and adolescents, 16% reported avoiding foods due to intolerance, whereas 12% avoided certain foods in an effort to improve their health. However, more than half of the participants who reported intolerance did not receive a medical assessment for proper diagnosis. Whether the underlying cause was intolerance, functional disease, or lifestyle, that study showed there was a considerable number of children and adolescents who avoided foods without professional medical guidance. This could have a negative impact on their health and underscores the need for pediatricians to recognize this situation and ensure that food restrictions and specific diets are adequately addressed. Recommending counseling by a pediatric nutritionist, when necessary, is crucial in this age group.126 Breastfeeding should never be suspended in infants, when attempting to reduce lactose consumption, and the use of infant formulas reduced in lactose should be individualized and implemented only under precise indications.123

24. Lactase enzyme use is a recommended strategy for improving lactose digestion in children older than one year of age with LI.

Agreement percentage: 78.9% complete agreement, 21.1% partial agreement.

Quality of evidence: Low.

Strength of the recommendation: Weak for the intervention.

Lactase supplementation reduces symptoms, such as bloating, flatulence, and diarrhea, and is a viable option for children above six months and under two years of age. It is important to keep in mind that LI in that population is usually transient and secondary to an acute event, and so treatment should be directed at the underlying cause. In children under six months of age, lactase has been proposed for treating infant colic, but its indication still lacks clear evidence, making its use in this context controversial.127 Even so, the recommended doses are:

• •

  Infants and young children (<6 years of age): 3,000–9,000 FCC units per milk or dairy product intake

• •

  Older children (>6 years of age): 6,000–12,000 FCC units per intake, adjusted according to quantity of lactose ingested and clinical response. Presentation can be:

• •

  Drops: added to milk before its consumption, ideally letting the milk then stand for 30−60 minutes, for better lactose hydrolysis

• •

  Tablets/chewables: administered right before dairy product consumption, allowing the enzyme to act in the small bowel

• •

  Capsules: used in older children, according to individual swallowing ease and tolerance

25. In pediatrics, vitamin D and calcium supplementation should be given, whenever dairy products are suspended.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement.

Quality of evidence: Moderate.

Strength of the recommendation: Strong for the intervention.

In school-aged children and adolescents with LI, a personalized diet is recommended that includes low-lactose or fermented dairy products, such as yogurt, to ensure adequate calcium and vitamin D supply. If said products cannot be ingested, vitamin D and calcium supplementation should always be evaluated. Even when the underlying cause is not clear, whether intolerance, functional disease, or lifestyle, many children and adolescents avoid foods, without receiving professional counseling, which may have a negative impact on their health. This underlines the need for pediatricians to be aware of such situations and ensure that food restrictions and specific diets are adequately managed. Recommending nutritional counseling, when necessary, is crucial in this age group.126

From a nutritional perspective, plant-based beverages that simulate milk are not a substitute for dairy products.

Agreement percentage: 84.2% complete agreement, 15.8% partial agreement; Quality of evidence: High; Strength of the recommendation: Strong for the intervention.

Despite the fact that plant-based beverages, as substitutes for milk or other dairy products, are in high demand by the population, whether due to LI or cow’s milk protein allergy, their nutritional content is not equal to that of dairy products and so should not be recommended as a milk substitute because they do not provide the quantity or quality of essential nutrients for guaranteeing adequate growth and development.128 These products should not be recommended as milk substitutes for children under five years of age. They must be fortified with vitamins and minerals to create a nutritional profile similar to that of dairy products, because alone they are not rich in calcium or other micronutrients expected from cow’s milk. Importantly, plant-based beverages are not similar to rice or soy-based infant formulas designed for children under 12 months of age because said dairy formulas contain the necessary nutrients for infant feeding and have precise indications. In addition, reducing lactose in the infant diet should not compromise caloric intake (avoid diluting infant formulas or suspending breast milk).129 Regarding the use of prebiotics and probiotics in children with LI, there is insufficient evidence to support their recommendation.

The present guideline establishes an essential reference for the diagnostic and therapeutic management of LIRDs by promoting an individualized, evidence-based approach, adapted to the Mexican context. Despite these advances, there are still important areas of opportunity that must be addressed. One is the need to update epidemiologic studies in Mexico, utilizing modern definitions and standardized tests, to more accurately estimate the true prevalence of hypolactasia, clinical LI, and lactose sensitivity across different regions and ethnic groups. Another is the validation of tests considered standards, such as the breath test, and new methodologies, such as urinary xylose measurement following gaxilose administration. Strengthening these lines of research will optimize the available diagnostic resources, prevent unnecessary dietary restrictions, and guarantee more effective, reasonable, and patient-centered care for individuals with LIRDs.

No type of informed consent was required for the writing of this clinical Guideline, given that no type of confidential patient data or human subjects were included.

There were no ethical aspects to consider.

No financial support was received in relation to this study/article.