Lactose Intolerance

Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the adsorptive cells in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and flatulence. The diagnosis of LI can be suspected clinically based on symptoms after consumption of a lactose-containing meal. The most commonly used test for confirmation of the diagnosis is the lactose hydrogen breath test. The treatment goal is to eliminate symptoms while maintaining sufficient intake of calcium and vitamin D. Alternative diagnoses to LI should always be sought, as many people wrongly attribute their symptoms to LI.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology

  • In children: low prevalence at < 6 years of age → genetically regulated reductions of lactase activity begin after weaning off breast milk
  • In adults:
    • > 70% of adults worldwide have primary lactase deficiency (LD), but less than half of all adults have lactose intolerance (LI).
    • Lowest prevalence of LD: Northern Europeans
    • Highest prevalence of LD: Africans, African Americans, Asians, Asian Americans, Hispanics, and Native Americans

Etiology

Primary LD

  • Also called acquired primary lactase deficiency, lactase non-persistence, and primary adult hypolactasia
  • Most common type of LD (> 70% adults); a genetically determined epigenetic regulation Epigenetic regulation Epigenetic regulation is regulation of gene expression that does not involve alterations to the DNA sequence or any of its transcribed products. The most common forms of epigenetic regulation are DNA methylation, which suppresses gene expression, and modifications to the histone proteins, which affect the structure of DNA packaging. Epigenetic Regulation of the lactase gene that decreases, either partially or completely, lactase activity after weaning 
  • More than half of people with primary LD do not have LI.

Secondary LD

  • A decrease in lactase and other brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes as well as abnormalities in transport processes
  • Due to small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine infection or a primary mucosal disease such as celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease

Less common types of LD

  • Congenital (e.g., rare deficiency of lactase)
  • Developmental: in premature infants, since lactase activity develops late in gestation

Pathophysiology

General consideration

  • Adults: Most have primary LD, but the majority do not develop LI.
  • Infants: all infants have lactase, which digests lactose → the most abundant carbohydrate in breast milk (accounts for 40% of calories in the milk).
  • Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates are only absorbed in the small bowel and only as monosaccharides.

Lactase

  • One of the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the brush border of the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
  • Digests lactose into glucose and galactose, which are actively transported into the enterocytes by the sodium/glucose (galactose) co-transporter (SGLT1)
  • Lactase activity falls during weaning and does not persist after 6 years of age in > 70% of people, causing primary LD but not necessarily LI.
  • In secondary LD, the activity levels of other enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and transport processes also fall, secondary to infections or inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the small bowel.

Effects of undigested lactose

  • Undigested lactose causes an osmotic load that pulls water and electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes into the bowel → watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Gas is produced by bacterial fermentation of lactose in the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix (hydrogen, carbon dioxide, and methane):
    • Results in excessive bloating, flatulence, and abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Colonic adaptation or “enhanced colonic lactose processing”: a reduction of intolerance symptoms, likely related to a change in microbiome → reduction of symptoms
  • The likelihood of developing symptoms after lactose ingestion depends on a number of factors.
Pathogenesis of lactose intolerance symptoms

Pathogenesis of LI symptoms:
The likelihood of a person with primary LD developing symptoms after lactose ingestion depends on a number of factors.

Image by S. Oiseth, Lecturio.

Clinical Presentation

Children and adolescents

  • Uncommon to show signs of LI under 6 years of age
  • Diarrhea, with bulky, frothy, and watery stools
  • Inability to gain weight
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Bloating
  • Flatulence
  • Nausea
  • Vomiting

Adults

  • Symptoms depend on multiple factors, including lactose load: usually requires ingestion of > 480 mL (2 cups) of milk
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
  • Bloating
  • Flatulence
  • Nausea
  • Vomiting
  • Diarrhea is rare in adults.

Diagnosis

Consider a diagnosis of LI if typical symptoms occur within a few hours after ingestion of a lactose-containing meal and resolve after 5–7 days.

Testing for LD

Note: Tests for LD alone do not confirm LI unless symptoms are also provoked by lactose loading.

  • Validated questionnaire
  • Lactose hydrogen breath test:
    • Measures lactose malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion
    • Testing method in adults: 
      • Give 50 g of lactose orally and sample breath hydrogen at baseline and every 30 minutes for 3–4 hours. 
      • A rise in hydrogen concentration of 20 parts per million (ppm) over baseline is diagnostic of lactose malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion.
      • Sensitivity: 78%; specificity: 98%
  • Small bowel biopsy: 
    • The diagnostic gold standard but rarely performed because it is invasive 
    • Can help distinguish between primary and secondary LD

Secondary causes of LD

Always consider potential secondary causes of LD when making the diagnosis:

  • Infectious enteritis, including giardiasis Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis
  • Celiac disease
  • Inflammatory bowel disease (especially Crohn’s disease)
  • Drug- or radiation-induced enteritis
  • Secondary intestinal bacterial overgrowth

Management

Primary lactose intolerance

  • Lactose restriction:
    • Reduce load to ≤ 480 mL (2 cups) of milk or equivalent per day. 
    • Should be consumed with other food to delay gastric emptying
    • Routine daily consumption of lactose is better than intermittent intake due to colonic adaptation. 
    • Milk and ice cream deliver the highest lactose loads: High-fat content can mitigate symptoms as it decreases gastric emptying rate.
    • Cheeses: usually contain lower amounts of lactose
    • Live-culture yogurt contains endogenous lactase → breaks down lactose into galactose and glucose
  • Substitute regular dairy products with predigested ones, or vegan products.
  • Lactase enzyme preparations: do not completely hydrolyze ingested lactose; efficacy highly variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables
  • Increase consumption of calcium and vitamin D, with supplements if necessary, if patient avoids all dairy products → monitor blood levels

Secondary lactose intolerance

Treat the primary disorder. It may take months for normal lactase activity to return to normal.

Differential Diagnosis

  • Cow’s milk allergy: the most common food allergy in young children but uncommon in adults. Cow’s milk proteins can provoke IgE-mediated and/or non-IgE-mediated immune response. Diagnosis is made by testing for specific IgE antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins and/or by elimination diet.
  • Food protein intolerance: can present with similar symptoms as LI due to unabsorbed substrate in the intestine. Although the temporal association of the symptoms with the type of food ingested can point toward the responsible food product, the best way to differentiate between the 2 conditions is via hydrogen breath test or trial of a lactose-free diet.
  • Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome: can present with similar symptoms (abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, bloating, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea) and may worsen coexisting LI, but the temporal association of the symptoms only with the ingestion of lactose products points toward lactose intolerance. The best way to differentiate between the 2 conditions is by a hydrogen breath test or trial of a lactose-free diet.
  • Pediatric diarrhea Pediatric diarrhea Diarrhea is described as passage of large amounts stools that are often loose, liquid, or watery, resulting in excess loss of fluids and electrolytes. Diarrhea is one of the most common illnesses in children, representing the largest percentages of morbidity and mortality worldwide in the pediatric age group. Pediatric Diarrhea: has many potential causes, including secretory and osmotic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, motility disorders, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea due to decreased surface area. Multiple diagnostic tools are available.
  • Incomplete absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of orally ingested simple carbohydrates: these carbohydrates include sorbitol, mannitol, xylitol, fructose, and FODMAPs (fermentable oligo-, di-, monosaccharides, and polyols). Sorbitol, mannitol, and xylitol are used as artificial sweeteners, and mannitol is used as a laxative. Diagnosis is usually straightforward based on the dietary history or a breath test for fructose.

References

  1. Hammer, H.F., Högenauer, S. (2020). Lactose intolerance: Clinical manifestations, diagnosis, and management. UpToDate. Retrieved December 18, 2020, from https://www.uptodate.com/contents/lactose-intolerance-clinical-manifestations-diagnosis-and-management
  2. Binder, H.J.  (2018). Disorders of absorption/carbohydrates. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, p. 2248).
  3. Seetharam, B., Perrillo, R., Alpers, D.H. (1980). Effect of pancreatic proteases on intestinal lactase activity. Gastroenterology. 1980 Nov;79(5 Pt 1):827-32. PMID: 6774905.
  4. Suarez, F.L., Savaiano, D.A., Levitt, M.D. (1995). A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. The New England Journal of Medicine, 333(1), 1–4.
  5. Gerbault, P., Liebert, A., Itan, Y., Powell, A., Currat, M., Burger, J., Swallow, D.M., Thomas, M.G. (2011). Evolution of lactase persistence: an example of human niche construction. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 366(1566), 863–877. https://doi.org/10.1098/rstb.2010.0268
  6. Forsgård R. A. (2019). Lactose digestion in humans: intestinal lactase appears to be constitutive whereas the colonic microbiome is adaptable. The American Journal of Clinical Nutrition, 110(2), 273–279. https://doi.org/10.1093/ajcn/nqz104

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