Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management

Abstract

Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.

Keywords: diet; functional bowel disorder; hydrogen breath tests; lactase; malabsorption.

Figure 1

Physiology of lactose malabsorption. SCFA, short chain fatty acids.

Figure 2

Worldwide prevalence of lactose malabsorption. Online supplement 1 breaks down the the evidence base in terms of the investigative modality used to acquire the epidemiological information (eg, genetic test and breath test). Online supplement 2 provides the complete reference list.

Figure 3

Schematic model of the pathogenesis of lactose intolerance symptoms. In a given population, a fraction of individuals will have digestive dysfunction resulting in lactose malabsorption. Within this population, individuals with anxiety disorders or GI disease that increase visceral sensitivity are more susceptible to the lactose challenge. In this model, the risk of developing symptoms increases with lactose dose, severity of digestive dysfunction (lactose malabsorption) and visceral sensitivity. This model of disease is not restricted to lactose but is likely to be shared by other FODMAPs, fermentable oligosaccharides, disaccharides and monosaccharides and polyols.

Figure 4

Mechanistic model of lactose digestion in patients with lactase persistence and lactase deficiency illustrating the relationship between lactose malabsorption, visceral sensitivity and symptoms.

Figure 5

Genetics of lactose malabsorption. (A) Organisation of the lactase genetic locus on chromosome 2. The positions of the lactase gene (LCT) and the neighbouring genes aspartyl-tRNA synthetase (DARS), minichromosome maintenance complex component 6 (MCM6) and UBX domain-containing protein 4 (UBXN4) are indicated. Polymorphisms relevant for lactose malabsorption are located within intron 13 of the MCM6 gene, upstream of the lactase gene. (B) Differential levels of methylation of intron 13 of MCM6 and the LCT gene in individuals with genetic lactose malabsorption (LCT −13910:C/C), lactose tolerance (LCT −13910:T/T) and the clinically silent, physiologically intermediate genotype LCT −13910:C/T. Hypermethylation (red colour) results in genetic silencing of the respective gene. (Source: From Labrie et al 26).

Figure 6

Symptoms in individuals with lactose malabsorption depend on lactose dose and visceral hypersensitivity. A population of Chinese individuals (100% primary lactase non-persistence) including HV with no history of abdominal symptoms and individuals with IBS-D was tested three times with different lactose dosages (10, 20 and  40 g) in a blinded fashion. The likelihood of a clinically positive HBT was higher in individuals with IBS-D for the low and the intermediate lactose dose. HBT,  hydrogen breath test; HV, healthy volunteers; IBS-D, diarrhoea-predominant  irritable bowel syndrome.  (Source: Adapted from Yang et al.56)

Figure 7

Results of a hydrogen breath test of an individual with lactose intolerance with simultaneous assessment symptoms and H₂ levels, indicating lactose fermentation by the microbiota. An H₂ increase by ≥20 ppm over baseline indicates lactose malabsorption. When ¹³C-labelled lactose is administered, ¹³CO₂ levels indicate absorption and metabolisation of ¹³C-labelled lactose by the subject. Patient reports of abdominal symptoms subsequent to increases in these markers is diagnostic of lactose intolerance.

Figure 8

Management of lactose malabsorption and lactose intolerance. FODMAPs, fermentable oligosaccharides, disaccharides and monosaccharides and polyols.