Lactose intolerance and lactase deficiency

Primary hypolactasia

It was previously thought that lactase persistence in humans was inherited in a 'wild type' (most common phenotype in the natural population). More recently, lactase non-persistence has been considered to be of ancestral type (normal Mendelian inheritance), and lactase persistence due to mutation.[3][15][16] Lactase non-persistence in other mammals supports this.
Two single nucleotide polymorphisms (C/T13910 and G/A22018) have been associated with lactase persistence.[3][17] Evidence suggests that C/T13910 is the dominant polymorphism, with the C allele linked to a decline in lactase mRNA expression. However, the exact mechanism of this decline after weaning is unclear.[3][17]
The single nucleotide polymorphism, CC/GG, is associated with lactase non-persistence and lactose intolerance.

Secondary (acquired) hypolactasia

Results from loss of lactase activity in people with lactase persistence due to gastrointestinal illnesses that damage the brush border of the small intestine (e.g., viral gastroenteritis, giardiasis, coeliac disease).[14]
Endoplasmic reticulum stress (accumulation of misfolded proteins and alterations in calcium homeostasis in the endoplasmic reticulum leading to cell death) is one of the possible explanations of why loss of lactase persists after gut infections such as rotavirus.

Congenital hypolactasia

A single autosomal recessive disorder, although very little is known about the molecular basis.[18]
Early recognition and prompt treatment of this potentially life-threatening condition is of paramount importance.

Developmental hypolactasia

Related to suboptimal levels of lactase in the apical microvilli of the brush border surface of the small intestine in premature infants (as the mucosal structure has still not fully developed).[19]

In all mammals, lactase concentrations are at their highest shortly after birth and generally decline rapidly after the usual age of weaning. Lactose is a disaccharide sugar found in milk and processed foods. Lactose is digested by hydrolysis, which is considered a rate-limiting step for the overall process of its absorption. Lactose is split by lactase enzyme into glucose and galactose on the microvillus membrane of the small intestine absorptive cells. In patients with hypolactasia, lactose not absorbed by the small bowel due to the failure of effective hydrolysis (because of low lactase levels) passes rapidly into the colon as a consequence of the high osmolality of the intraluminal disaccharide. In the colon, lactose is converted to short-chain fatty acids and gas (hydrogen, methane, and carbon dioxide, etc.) by the lactic acid bacterial flora, producing acetate, butyrate, and propionate. It is the microbial lactase from the lactic acid bacteria (e.g., Lactobacillus, Bifidobacterium, Leuconostoc, Pediococcus) that initially breaks down unabsorbed lactose by hydrolysis to glucose and galactose, which are then absorbed or fermented as above. The short-chain fatty acids are absorbed by the colonic mucosa, and this route salvages malabsorbed lactose for energy use. It has been suggested that the production of potentially toxic agents (e.g., acetoin, acetaldehyde, butane 2,3 diol, ethanol, and indoles) in the large bowel may affect ionic signalling pathways in the nervous system, heart, other muscles, and the immune system, which may contribute to abdominal pain, distension, diarrhoea, flatulence, and other symptoms.[1][20][21][22]

The combined increase in osmolality of the faecal water, accelerated intestinal transit, and generated hydrogen and methane accounts for the wide range of gastrointestinal symptoms (e.g., abdominal pain, distension, diarrhoea, flatulence). Other factors related to the severity of symptoms include the rate of gastric emptying, fat content of the food in which the sugar is ingested, the individual sensitivity to intestinal distension produced by the osmotic load of unhydrolysed lactose in the small bowel, and the response of the colon to the carbohydrate load.

Hypolactasia does not always lead to lactose intolerance, as symptoms depend on the amount and rate of lactose reaching the colon, as well as the type and amount of colonic flora.[1]

Subgroups of lactase deficiency[2]

Primary (hereditary) hypolactasia

The most common cause of lactose malabsorption and lactose intolerance is due to lactase non-persistence
Has a prevalence of up to 100% in some ethnic groups (e.g., American Indians and some Asian populations)[4]
Physiological decline of lactase activity around the time of weaning causes a relative or absolute absence of lactase
Develops in childhood at various ages, although it is uncommon before 2-3 years of age.

Secondary (acquired) hypolactasia

Secondary to injury to the small intestinal mucosa
Small bowel causes include HIV enteropathy, regional enteritis, sprue (coeliac and tropical), Whipple's disease (intestinal lipodystrophy), and severe gastroenteritis
Multisystem causes include carcinoid syndrome, cystic fibrosis, diabetic gastropathy, kwashiorkor, and Zollinger-Ellison syndrome
Iatrogenic causes include chemotherapy, use of colchicines (in patients with familial Mediterranean fever), and radiation enteritis
Can present at any age but is more common in infancy.

Congenital hypolactasia

Extremely rare, lifelong disorder characterised by faltering growth and intractable diarrhoea from the first exposure to breast milk or lactose-containing formula milk
Affected infants have minimal or absent lactase activity.

Developmental hypolactasia

Relative lactase deficiency observed among preterm infants of <34 weeks' gestation
Due to underdeveloped mucosal structure of the small intestine
Rapidly improves as intestinal mucosa matures.

Pathophysiology

Classification

Subgroups of lactase deficiency[2]