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Lactose Intolerance
Introduction
Lactose intolerance is a clinical syndrome characterized by gastrointestinal symptoms, such as bloating, abdominal pain, flatulence, nausea, borborygmi, and diarrhea, following the ingestion of lactose-containing food.[1][2] Although often associated with lactose malabsorption, the 2 terms are not synonymous.
Lactose, a disaccharide and the primary sugar in human breast milk, is hydrolyzed into glucose and galactose by the enzyme lactase, located in the small intestinal border.[3][4] Galactose is critical for macromolecular synthesis, and human milk is its only natural dietary source. Lactase deficiency, the most common disaccharidase deficiency, is rarely congenital; it typically arises as a secondary process following intestinal injury or as a genetically programmed late-onset decline in enzyme activity.[5]
Lactase activity peaks postnatally and declines thereafter, irrespective of continued lactose intake. This pattern is conserved across most nonhuman mammals. Populations of South American, Asian, and African descent exhibit higher rates of adult-onset lactase deficiency. In contrast, those of northern European and northwestern Indian ancestry more commonly retain lactase activity into adulthood.[6]
Many individuals avoid lactose-containing foods upon symptom onset and diagnosis, often switching to lactose-free products and supplements. This dietary modification, even when based on a presumed rather than confirmed diagnosis, contributes to increased healthcare utilization.
Etiology
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Etiology
Lactase enzyme deficiency results from reduced enzyme activity, leading to impaired hydrolysis of lactose into absorbable glucose and galactose. Genetic factors contribute significantly, with specific single-nucleotide polymorphisms associated with lactose intolerance. In Northeastern Brazil, the distinct single-nucleotide polymorphisms correlate with lactase persistence. Among Indo-Europeans, the C/T 13910 (C>T) polymorphism plays a key role—the TT genotype is associated with lactase persistence, the C/T genotype with partial deficiency, and the CC genotype with complete deficiency.[7]
Lactase deficiency is classified into four types—primary (late-onset), secondary (acquired), developmental, and congenital. Each type varies in etiology, age of onset, and underlying pathology, with secondary deficiency being the most common and typically reversible following resolution of the underlying intestinal injury.
Primary Lactase Deficiency
Primary lactase deficiency, also known as lactase nonpersistence, is the most common form of lactase deficiency. There is a gradual decline in lactase enzyme activity with increasing age. Enzyme activity declines in infancy, and symptoms manifest in adolescence or early adulthood. More recently, it has been observed that lactase nonpersistence is of the ancestral form (normal Mendelian inheritance), and lactase persistence is secondary to mutation.[8][9][10]
Secondary Lactase Deficiency
Injury to the intestinal mucosa can lead to secondary lactase deficiency, and resolution of the underlying cause may resolve the lactose intolerance.[11] Common causes include:
- Gastrointestinal infections, such as those caused by rotavirus in children and Giardia lamblia
- Celiac disease
- Crohn disease
- Chemotherapy
- Antibiotics
- Small intestinal surgery
- Radiation therapy to the small intestine
Developmental Lactase Deficiency
Developmental lactase deficiency is observed in premature infants born at 28 to 37 weeks of gestation.[12] The infant's intestine is underdeveloped, resulting in inadequate lactase production. This condition improves with age due to the maturation of the intestine, which results in adequate lactase activity.
Congenital Lactase Deficiency
Congenital lactase deficiency is a rare autosomal recessive genetic condition due to mutations in the LCT gene, with only about 40 cases reported worldwide.[8] This condition results in decreased or absent lactase enzyme activity.[13][14] Symptoms appear shortly after birth with the ingestion of milk.[15]
Epidemiology
Lactose intolerance is common worldwide but rare in children younger than 5. This condition primarily affects adolescents and young adults, with equal prevalence across sexes. Globally, 65% to 70% of the population exhibits lactose intolerance, most commonly in its primary form,[16] though not all individuals are symptomatic.[17][18][19] Secondary lactase deficiency is more prevalent in children, especially in developing countries, due to infection-related enteropathy.[11] The onset of primary disease is typically gradual, with symptoms emerging in late adolescence or adulthood.[2][3] Earlier onset is more common in Native American, Asian, African-American, and Hispanic/Latino populations compared to White Northern Europeans, Australians, and North Americans.[20]
Lactose intolerance prevalence varies by ethnicity, being highest among African Americans, Hispanics/Latinos, and Asians, and lowest in individuals of European descent.[21] Populations with higher intolerance rates also exhibit greater frequencies of lactase nonpersistence genotypes.[22][23]
In the United States, primary lactose intolerance is significantly more prevalent among African-Americans, Asian Americans, and Native Americans, compared to White Americans.[20][21][24][25][26] The lowest rates are observed in North Americans, Australians, and White Northern Europeans, ranging between 2% and 15%.[20][24] In contrast, prevalence reaches 50% to 80% in South Americans, 60% to 80% in Ashkenazi Jews and Western Africans, and nearly 100% in American Indians and some East Asian populations.[20][25][26] High rates are also reported in Italy, Greece, and Arab countries.[27]
The age-related decline in lactase activity typically completes in childhood but may occur later in adolescence, particularly among Whites.[28] The rate and extent of this decline vary by ethnicity. In Chinese and Japanese populations, 80% to 90% of lactase activity is lost within 3 to 4 years after weaning. In Jewish and some Asain populations, 60% to 70% is lost more gradually over several years. For White Northern Europeans and North Americans, lactase levels may take 18 to 20 years to reach their lowest levels.[17] Individuals with mixed ethnicity tend to have lower rates of lactase nonpersistence compared to their native ethnic counterparts.
Pathophysiology
Salivary and pancreatic amylases initiate starch digestion by breaking it into smaller polysaccharides and monosaccharides. Lactase, located on the brush border of the small intestinal mucosa, hydrolyzes lactose into glucose and galactose, which are then absorbed through the SGLT1 and Glut-2 transporters.[29]
In lactase deficiency, undigested lactose remains in the intestinal lumen, where it undergoes bacterial fermentation in the distal small bowel and colon. This process produces volatile gases, including hydrogen, methane, carbon dioxide, hydrogen sulfide, and short-chain fatty acids. The accumulation of unabsorbed lactose increases intraluminal osmotic pressure, leading to fluid influx and osmotic diarrhea.[30]
These processes contribute to gastrointestinal symptoms of lactose intolerance and overlap with maldigestion of other fermentable carbohydrates—including oligosaccharides, disaccharides, monosaccharides, and polyols—as well as sucrose, fructose, and maltose. Symptoms are often more pronounced in individuals with delayed gastric emptying or visceral hypersensitivity, as observed in disorders of gut-brain interaction, such as functional dyspepsia and irritable bowel syndrome.[31][32]
Histopathology
In lactose intolerance, histopathologic findings in the small intestine vary depending on the underlying cause of lactase deficiency. In primary lactase deficiency, or when mucosal involvement is focal, the mucosa may appear normal.[33] Lactase activity can be measured to assess disease severity.
In secondary lactase deficiency, biopsy findings depend on the underlying pathology. For example, celiac disease may show villous blunting with inflammatory cell infiltration.
History and Physical
Symptoms of lactose intolerance typically appear 30 minutes to 2 hours after ingestion of lactose-containing foods. Symptom severity depends on the lactose dose, residual lactase activity, and small bowel transit time.[34] Clinicians should inquire about the onset of symptoms concerning high-lactose food intake.
Common signs and symptoms of lactose intolerance include:[35][36]
- Diarrhea
- Abdominal bloating
- Abdominal pain
- Nausea and vomiting
- Sensation of fullness
- Flatulence
Less commonly, patients may report systemic symptoms such as headache, muscle pain, joint pain, mouth ulcers, urinary symptoms, and impaired concentration.[37][38] The physical examination is often unremarkable but may reveal abdominal distention, tenderness, or tympany to percussion.
Evaluation
Symptom resolution following lactose elimination and recurrence upon reintroduction supports the diagnosis of lactose intolerance.[39] Further diagnostic testing may be warranted in cases of diagnostic uncertainty or when alternative conditions are suspected.
Diagnostic Tests
Diagnosis of lactose intolerance is primarily clinical but may be supported by noninvasive tests when uncertainty exists or to exclude other conditions. The following diagnostic modalities assess lactose malabsorption, enzyme activity, or genetic predisposition.
- Hydrogen breath test: This test measures breath hydrogen after lactose ingestion. An increase >20 ppm above baseline indicates lactose malabsorption.[40] Proper test protocols are essential for accuracy.[40]
- Stool acidity test: This test detects low stool pH due to fermentation of unabsorbed lactose into lactic acid.
- Milk tolerance test: After administering 500 mL of milk, a rise in blood glucose <9 mg/dL suggests lactose malabsorption.[41]
- Lactose tolerance test: This test involves ingestion of 50 g lactose with serial glucose measurements at 0, 60, and 120 minutes.[40] A rise <20 mg/dL suggests lactose intolerance. Sensitivity is 75%; specificity is 96%. False-negative results may occur in patients with diabetes mellitus or small intestinal bacterial overgrowth. The results are also affected by delayed gastric emptying.[42]
- Small bowel biopsy: This test is invasive and rarely used; reserved for excluding secondary causes such as celiac disease.
- Genotyping: Genotyping is emerging as a highly sensitive and specific test. This test is currently more common in Germany and Nordic countries, but not widely adopted elsewhere.[43]
Proper Performance of Hydrogen Breath Testing
- Use only certified medical-grade testing products.
- Store and handle breath samples according to the manufacturer's guidelines.
- In young children, use a face mask or a suitable device for complete sample collection.
- Avoid taking antibiotics for at least 4 weeks before testing.
- Do not perform testing within 2 weeks of bowel preparation for colonoscopy or surgery.
- Avoid dietary fiber and FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) for 24 hours before testing, as they can elevate baseline hydrogen levels.
- Discontinue lactulose, lactose, laxatives, prokinetics, and probiotics 24 hours before and during testing.
- Infants should fast for at least 4 hours; children and adults should fast for at least 8 hours.
- Refrain from smoking for at least 2 hours before and during testing.
- Minimize physical activity 2 hours before and during testing to prevent hyperventilation.
- Perform a chlorhexidine oral rinse before collecting the initial breath sample.[44]
Treatment / Management
Management of lactose intolerance includes dietary modification, lactase supplementation, and treatment of underlying causes in secondary lactase deficiency. Complete lactose elimination is rarely required, as most individuals tolerate up to 15 g of lactose daily, especially when consumed with other foods.[45]
Dietary Modification
Lactase-containing dairy products and calcium supplementation are recommended. Reducing lactose intake can decrease colonic hydrogen production and alleviate symptoms. Although strict avoidance is not always necessary, the following lactose-containing foods should be limited or avoided:
- Cow, goat, and sheep milk
- Ice cream and sherbet
- Butter and margarine
- Buttermilk, whipping cream, sour cream, and coffee creamers
- Soft cheeses, such as cream cheese, cottage cheese, ricotta, and mascarpone
- Evaporated milk, condensed milk, and milk powder
- Pudding and custard
- Whey protein, especially whey concentrate
- Pancakes and waffles, if prepared with milk or butter
Yogurt contains variable amounts of lactose and may trigger symptoms in some individuals. Greek yogurt has the lowest lactose content. Live yogurt cultures produce β-galactosidase, which may enhance lactose digestion in vivo.[46] Plant-based milk alternatives, such as almond, coconut, and soy, are lactose-free options, although concerns remain regarding palatability, nutritional adequacy, and processing challenges.[47][48]
Probiotics, such as the Lactobacillus acidophilus DDS-1 strain, have shown potential in alleviating symptoms.[49][50] Calcium and vitamin D supplementation are recommended to maintain bone health. In secondary lactase deficiency, management should also address the underlying condition.[45](A1)
Lactase Supplements
Lactase enzyme supplements extracted from yeasts and molds are available as tablets or drops. In most cases, these supplements should be taken just before eating a high-lactose product or with the first bite. However, when drops are added to milk, they should be shaken or stirred and refrigerated for 24 hours before ingestion to allow the lactose to break down.
Differential Diagnosis
Several conditions may mimic or coexist with lactose intolerance and should be considered in the differential diagnosis:
- Irritable bowel syndrome
- Functional dyspepsia
- Celiac disease
- Tropical sprue
- Inflammatory bowel disease
- Small intestinal diverticula
- Intestinal neoplasm or polyp
- Excessive ingestion of laxatives
- Viral gastroenteritis
- Bacterial infection
- Giardiasis
- Gastrinoma
- Cystic fibrosis
Pertinent Studies and Ongoing Trials
Emerging treatments for lactose intolerance aim to improve symptom control and expand dietary flexibility beyond traditional lactase supplementation and dietary restriction. These strategies include novel enzyme therapies and advancements in personalized nutrition.
Fungal Beta-Galactosidases
Two fungal beta-galactosidases derived from Aspergillus carbonarius ATCC6276 (beta-gal 1 and beta-gal 2) have shown potential as enzyme supplements for lactose intolerance. Administered alone or in combination, these purified enzymes demonstrate greater stability under simulated gastric conditions compared to current commercial lactase preparations.[51]
Nutrigenomics
Nutrigenomics offers a future approach to managing hypolactasia by identifying specific genetic mutations or haplotype patterns that influence individual dietary responses, enabling more personalized nutritional interventions.[52]
Prognosis
Lactose intolerance carries an excellent prognosis, with most patients achieving a substantial symptom relief through dietary modification alone. However, untreated lactose malabsorption may contribute to osteopenia.[53][54][55] Vitamin D deficiency is linked to the LCT-13910C>T gene variant of lactose intolerance among Whites.[55]
Complications
Complications of lactose intolerance are uncommon but may arise from prolonged dietary restriction or untreated malabsorption. These complications include the following:
- Osteopenia
- Osteoporosis [21]
- Malnutrition
- Weight loss
- Rickets
- Growth failure
Consultations
Once lactose intolerance is diagnosed, referral to a dietitian is recommended for individualized dietary modification and nutritional counseling. A gastroenterologist should be consulted to evaluate for alternative or concurrent gastrointestinal disorders. Ongoing follow-up is essential to monitor symptom control and prevent potential dietary deficiencies.
Deterrence and Patient Education
Patients and their families should be counseled that consuming lactose-containing products typically causes only reversible symptoms and does not result in permanent gastrointestinal damage, unlike celiac disease. Long-term complications are unlikely when nutritional requirements, including adequate protein, caloric, calcium, and vitamin D intake, are maintained.[20]
Primary and congenital lactase deficiencies are not preventable. However, secondary lactase deficiency may be prevented through early diagnosis and treatment of underlying causes to preserve intestinal mucosal integrity. Limiting lactose-containing foods can further reduce symptom burden and disease impact.
Pearls and Other Issues
Table 1. Key Points to Remember About Lactose Intolerance
| Feature | Key Facts |
| Definition |
Inability to digest lactose due to lactase deficiency in the small intestinal brush border |
| Normal function |
Lactase hydrolyzes lactose → glucose + galactose → absorbed via SGLT1 |
| Pathophysiology |
Unabsorbed lactose → fermented by colonic bacteria → gas + osmotic diarrhea |
| Types |
Primary: Most common, age-related decline after weaning Secondary: Intestinal mucosal injury (celiac, gastroenteritis, giardiasis, irritable bowel disease, and chemotherapy) Developmental: Premature infants (improves with age) Congenital: Rare, newborn onset |
| Epidemiology |
Affects 65%-70% globally Rare before 5 years Common in Asian, African, Hispanic, and Native American Rare in Northern Europeans |
| Symptoms |
30 min to 2 h after lactose ingestion Bloating, cramps, flatulence, and osmotic diarrhea Severity is dose-dependent |
| Diagnosis |
Clinical: Symptom relief with lactose elimination, recurrence on challenge Hydrogen breath test: ↑ >20 ppm from baseline, stool pH <5.5 (children) Lactose tolerance test: <20 mg/dL rise in glucose Small bowel biopsy for secondary causes Genetic testing for lactase nonpersistence |
| Management |
Limit lactose (most tolerate ≤15 g/d with food) Lactase enzyme supplements Lactose-free dairy or plant-based alternatives Ensure calcium and vitamin D intake Treat the underlying cause if secondary |
| Complications |
Rare if the diet is adequate Osteopenia or osteoporosis if low calcium and vitamin D [56] |
| Pearls |
Osmotic diarrhea: Low pH, high osmotic gap (>100) Primary form: Post-childhood onset in non-Europeans Secondary form: After mucosal injury Congenital form: Newborn after milk feeding Developmental form: Prematurity, improves with maturity |
Enhancing Healthcare Team Outcomes
The diagnosis and management of lactose intolerance require an interprofessional team, including a primary care provider, nurse practitioner, pediatrician, gastroenterologist, dietitian, and, when indicated, an allergist. The primary care provider or pediatrician typically initiates evaluation and distinguishes lactose intolerance from other gastrointestinal conditions. A gastroenterologist may be involved when symptoms are persistent or the diagnosis is unclear.
Dietitians play a central role in formulating personalized, well-balanced low-lactose or lactose-free diets while ensuring adequate intake of calcium, vitamin D, and other key nutrients. Pharmacists provide guidance on the proper use of lactase enzyme supplements and help identify hidden lactose in medications. Referral to an allergist is important if a milk allergy—an immune-mediated reaction to milk proteins—is suspected, as this condition is often confused with lactose intolerance. Effective collaboration among team members ensures comprehensive care, reduces unnecessary dietary restrictions, and promotes long-term patient well-being.
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