Lactose intolerance

Lactose intolerance is caused by a lessened ability or a complete inability to digest lactose, a sugar found in dairy products.^[1] Humans vary in the amount of lactose they can tolerate before symptoms develop.^[1] Symptoms may include abdominal pain, bloating, diarrhea, flatulence, and nausea.^[1] These symptoms typically start thirty minutes to two hours after eating or drinking something containing lactose,^[1] with the severity typically depending on the amount consumed.^[1] Lactose intolerance does not cause damage to the gastrointestinal tract.^[2]

Lactose intolerance is due to the lack of the

Lactose intolerance primarily refers to a syndrome with one or more symptoms upon the consumption of food substances containing lactose sugar. Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms.

Hypolactasia is the term specifically for the

Lactose intolerance is not an allergy, because it is not an immune response, but rather a sensitivity to dairy caused by a deficiency of lactase enzyme. Milk allergy, occurring in about 2% of the population, is a separate condition, with distinct symptoms that occur when the presence of milk proteins trigger an immune reaction.^[15]

Signs and symptoms

The principal manifestation of lactose intolerance is an adverse reaction to products containing lactose (primarily milk), including abdominal

Because lactose intolerance is not an allergy, it does not produce allergy symptoms (such as itching, hives, or anaphylaxis).

Causes

Lactose intolerance is a consequence of

Lactose intolerance in infants (congenital lactase deficiency) is caused by mutations in the LCT gene. The LCT gene provides the instructions for making lactase. Mutations are believed to interfere with the function of lactase, causing affected infants to have a severely impaired ability to digest lactose in breast milk or formula.[19] Lactose intolerance in adulthood is a result of gradually decreasing activity (expression) of the LCT gene after infancy, which occurs in most humans. The specific DNA sequence in the MCM6 gene helps control whether the LCT gene is turned on or off.^[20] At least several thousand years ago, some humans developed a mutation in the MCM6 gene that keeps the LCT gene turned on even after breast feeding is stopped.^[21] Populations that are lactose intolerant lack this mutation. The LCT and MCM6 genes are both located on the long arm (q) of chromosome 2 in region 21. The locus can be expressed as 2q21.^[21] The lactase deficiency also could be linked to certain heritages and varies widely. A 2016 study of over 60,000 participants from 89 countries found regional prevalence of lactose malabsorption was "64% (54–74) in Asia (except Middle East), 47% (33–61) in eastern Europe, Russia, and former Soviet Republics, 38% (CI 18–57) in Latin America, 70% (57–83) in the Middle East, 66% (45–88) in northern Africa, 42% (13–71) in northern America, 45% (19–71) in Oceania, 63% (54–72) in sub-Saharan Africa, and 28% (19–37) in northern, southern and western Europe."^[5] According to Johns Hopkins Medicine, lactose intolerance is more common in Asian Americans, African Americans, Mexican Americans, and Native Americans.^[22] Analysis of the DNA of 94 ancient skeletons in Europe and Russia concluded that the mutation for lactose tolerance appeared about 4,300 years ago and spread throughout the European population.^[23]

Some human populations have developed lactase persistence, in which lactase production continues into adulthood probably as a response to the benefits of being able to digest milk from farm animals. Some have argued that this links intolerance to natural selection favoring lactase-persistent individuals, but it is also consistent with a physiological response to decrease lactase production when it is not needed in cultures in which dairy products are not an available food source.^[24] Although populations in Europe, India, Arabia, and Africa were first thought to have high rates of lactase persistence because of a single mutation, lactase persistence has been traced to a number of mutations that occurred independently.^[11] Different alleles for lactase persistence have developed at least three times in East African populations, with persistence extending from 26% in Tanzania to 88% in the Beja pastoralist population in Sudan.^[25]

The accumulation of epigenetic factors, primarily DNA methylation, in the extended LCT region, including the gene enhancer located in the MCM6 gene near C/T-13910 SNP, may also contribute to the onset of lactose intolerance in adults.^[26][27] Age-dependent expression of LCT in mice intestinal epithelium has been DNA methylation in the gene enhancer.^[27]

Lactose intolerance is classified according to its causes as:

Primary hypolactasia

Primary hypolactasia, or primary lactase deficiency, is genetic, develops in childhood at various ages, and is caused by the absence of a lactase persistence allele. In individuals without the lactase persistence allele, less lactase is produced by the body over time, leading to hypolactasia in adulthood.^[2][28] The frequency of lactase persistence, which allows lactose tolerance, varies enormously worldwide, with the highest prevalence in Northwestern Europe, declines across southern Europe and the Middle East and is low in Asia and most of Africa, although it is common in pastoralist populations from Africa.^[9]

Secondary hypolactasia

Secondary hypolactasia or secondary lactase deficiency, also called acquired hypolactasia or acquired lactase deficiency, is caused by an injury to the

intestinal parasites (such as giardia), or other environmental causes.^{[2][31][32][33]}

Primary congenital alactasia

Primary congenital alactasia, also called congenital lactase deficiency, is an extremely rare,

autosomal recessive enzyme defect that prevents lactase expression from birth.^[2] People with congenital lactase deficiency cannot digest lactose from birth, so cannot digest breast milk. This genetic defect is characterized by a complete lack of lactase (alactasia). About 40 cases have been reported worldwide, mainly limited to Finland. Before the 20th century, babies born with congenital lactase deficiency often did not survive,^[2] but death rates decreased with soybean-derived infant formulas and manufactured lactose-free dairy products.^[34]

In order to assess lactose intolerance, intestinal function is challenged by ingesting more dairy products than can be readily digested. Clinical symptoms typically appear within 30 minutes, but may take up to two hours, depending on other foods and activities.[35] Substantial variability in response (symptoms of nausea, cramping, bloating, diarrhea, and flatulence) is to be expected, as the extent and severity of lactose intolerance varies among individuals.^{[citation needed]}

The next step is to determine whether it is due to primary lactase deficiency or an underlying disease that causes secondary lactase deficiency.^[2] Physicians should investigate the presence of undiagnosed coeliac disease, Crohn's disease, or other enteropathies when secondary lactase deficiency is suspected and infectious gastroenteritis has been ruled out.^[2]

Lactose intolerance is distinct from milk allergy, an immune response to cow's milk proteins. They may be distinguished in diagnosis by giving lactose-free milk, producing no symptoms in the case of lactose intolerance, but the same reaction as to normal milk in the presence of a milk allergy. A person can have both conditions. If positive confirmation is necessary, four tests are available.^[36]

Hydrogen breath test

In a hydrogen breath test, the most accurate lactose intolerance test, after an overnight fast, 25 grams of lactose (in a solution with water) are swallowed. If the lactose cannot be digested, enteric bacteria metabolize it and produce hydrogen, which, along with methane, if produced, can be detected on the patient's breath by a clinical gas chromatograph or compact solid-state detector. The test takes about 2.5 hours to complete. If the hydrogen levels in the patient's breath are high, they may have lactose intolerance. This test is not usually done on babies and very young children, because it can cause severe diarrhea.^[37]

Lactose tolerance test

In conjunction, measuring blood glucose level every 10 to 15 minutes after ingestion will show a "flat curve" in individuals with lactose malabsorption, while the lactase persistent will have a significant "top", with a typical elevation of 50% to 100%, within one to two hours. However, due to the need for frequent blood sampling, this approach has been largely replaced by breath testing.^[38]

After an overnight fast, blood is drawn and then 50 grams of lactose (in aqueous solution) are swallowed. Blood is then drawn again at the 30-minute, 1-hour, 2-hour, and 3-hour marks. If the lactose cannot be digested, blood glucose levels will rise by less than 20 mg/dl.^[39]

Stool acidity test

This test can be used to diagnose lactose intolerance in infants, for whom other forms of testing are risky or impractical.^[40] The infant is given lactose to drink. If the individual is tolerant, the lactose is digested and absorbed in the small intestine; otherwise, it is not digested and absorbed, and it reaches the colon. The bacteria in the colon, mixed with the lactose, cause acidity in stools. Stools passed after the ingestion of the lactose are tested for level of acidity. If the stools are acidic, the infant is intolerant to lactose.^[41] Stool pH in lactose intolerance is less than 5.5.

Intestinal biopsy

An intestinal biopsy must confirm lactase deficiency following discovery of elevated hydrogen in the hydrogen breath test.

Stool sugar chromatography

Chromatography can be used to separate and identify undigested sugars present in faeces. Although lactose may be detected in the faeces of people with lactose intolerance, this test is not considered reliable enough to conclusively diagnose or exclude lactose intolerance.^{[citation needed]}

Genetic diagnostic

Genetic tests may be useful in assessing whether a person has primary lactose intolerance. Lactase activity persistence in adults is associated with two polymorphisms: C/T 13910 and G/A 22018 located in the MCM6 gene.^[28] These polymorphisms may be detected by molecular biology techniques at the DNA extracted from blood or saliva samples; genetic kits specific for this diagnosis are available. The procedure consists of extracting and amplifying DNA from the sample, following with a hybridation protocol in a strip. Colored bands are obtained as result, and depending on the different combinations, it would be possible to determine whether the patient is lactose intolerant. This test allows a noninvasive definitive diagnostic.^{[citation needed]}

Frequency

Lactose intolerance is most common in people of East Asian descent, with 70 to 100 percent of people affected in these communities. Lactose intolerance is also more common in people of West African, Arab, and Jewish descent, while only about 5 percent of people of northern European descent are lactose intolerant.^[19]

Management

When lactose intolerance is due to secondary lactase deficiency, treatment of the underlying disease may allow lactase activity to return to normal levels.^[6] In people with celiac disease, lactose intolerance normally reverts or improves several months after starting a gluten-free diet, but temporary dietary restriction of lactose may be needed.^[4][44]

People with primary lactase deficiency cannot modify their body's ability to produce lactase.^[1] In societies where lactose intolerance is the norm, it is not considered a condition that requires treatment. However, where dairy is a larger component of the normal diet, a number of efforts may be useful. There are four general principles in dealing with lactose intolerance: avoidance of dietary lactose, substitution to maintain nutrient intake, regulation of calcium intake, and use of enzyme substitute.^[42] Regular consumption of dairy food by lactase deficient individuals may also reduce symptoms of intolerance by promoting colonic bacteria adaptation.^[45]

Dietary avoidance

The primary way of managing the symptoms of lactose intolerance is to limit the intake of lactose to a level that can be tolerated.^[46] Lactase deficient individuals vary in the amount of lactose they can tolerate,^[1] and some report that their tolerance varies over time, depending on health status and pregnancy.^[47][48] However, as a rule of thumb, people with primary lactase deficiency and no small intestine injury are usually able to consume at least 12 grams of lactose per sitting without symptoms, or with only mild symptoms, with greater amounts tolerated if consumed with a meal or throughout the day.^[1][48][45]

Lactose is found primarily in dairy products, which vary in the amount of lactose they contain:

• Milk – unprocessed cow's milk is about 4.7% lactose;
  yak milk 4.93%.^[53]
• Sour cream and buttermilk – if made in the traditional way, this may be tolerable, but most modern brands add milk solids.[54]
• Yogurt – lactobacilli used in the production of yogurt metabolize lactose to varying degrees, depending on the type of yogurt.^[55] Some bacteria found in yogurt also produce their own lactase, which facilitates digestion in the intestines of lactose intolerant individuals.^[45]
• Cheese – The
  hard cheeses, which have a long ripening period, contain virtually no lactose:^[56] cheddar contains less than 1.5% of the lactose found in an equivalent mass of milk.^[49] However, manufactured cheeses may be produced using processes that do not have the same lactose-reducing properties.^[57]

There used to be[58] a lack of standardization on how lactose is measured and reported in food. The different molecular weights of anhydrous lactose or lactose monohydrate result in up to 5% difference.^[59] One source recommends using the "carbohydrates" or "sugars" part of the nutritional label as surrogate for lactose content,^[56] but such "lactose by difference" values are not assured to correspond to real lactose content.^[58] The stated dairy content of a product also varies according to manufacturing processes and labelling practices, and commercial terminology varies between languages and regions.^[42] As a result, absolute figures for the amount of lactose consumed (by weight) may not be very reliable.

Plant-based milks and derivatives such as soy milk, rice milk, almond milk, coconut milk, hazelnut milk, oat milk, hemp milk, macadamia nut milk, and peanut milk are inherently lactose-free. Low-lactose and lactose-free versions of foods are often available to replace dairy-based foods for those with lactose intolerance.^[65]

Lactase supplements

When lactose avoidance is not possible, or on occasions when a person chooses to consume such items, then enzymatic lactase supplements may be used.^[66][67]

Lactase enzymes similar to those produced in the small intestines of humans are produced industrially by

While essentially the same process as normal intestinal lactose digestion, direct treatment of milk employs a different variety of industrially produced lactase. This enzyme, produced by yeast from the genus Kluyveromyces, takes much longer to act, must be thoroughly mixed throughout the product, and is destroyed by even mildly acidic environments. Its main use is in producing the lactose-free or lactose-reduced dairy products sold in supermarkets.^[69]

Rehabituation to dairy products

Regular consumption of dairy foods containing lactose can promote a colonic bacteria adaptation, enhancing a favorable microbiome, which allows people with primary lactase deficiency to diminish their intolerance and to consume more dairy foods.^[45][48][70] The way to induce tolerance is based on progressive exposure, consuming smaller amounts frequently, distributed throughout the day.^[71] Lactose intolerance can also be managed by ingesting live yogurt cultures containing lactobacilli that are able to digest the lactose in other dairy products.^[72]

Epidemiology

Worldwide, about 65% of people experience some form of lactose intolerance as they age past infancy, but there are significant differences between populations and regions. As few as 5% of northern Europeans are lactose intolerant, while as many as 90% of adults in parts of Asia are lactose intolerant.^[74]

In northern European countries, early adoption of dairy farming conferred a selective evolutionary advantage to individuals that could tolerate lactose. This led to higher frequencies of lactose tolerance in these countries. For example, almost 100% of Irish people are predicted to be lactose tolerant.^[75] Conversely, regions of the south, such as Africa, did not adopt dairy farming as early and tolerance from milk consumption did not occur the same way as in northern Europe.^[45] Lactose intolerance is common among people of Jewish descent, as well as from West Africa, the Arab countries, Greece, and Italy.^[74] Different populations will present certain gene constructs depending on the evolutionary and cultural pre-settings of the geographical region.^[45]

History

Greater lactose tolerance has come about in two ways.^[76] Some populations have developed genetic changes to allow the digestion of lactose: lactase persistence.^[76] Other populations developed cooking methods like milk fermentation.^[76]

Lactase persistence in humans evolved relatively recently (in the last 10,000 years) among some populations. Around 8,000 years ago in modern-day Turkey, humans became reliant on newly-domesticated animals that could be milked; such as cows, sheep, and goats. This resulted in higher frequency of lactase persistence.^[77] Lactase persistence became high in regions such as Europe, Scandinavia, the Middle East and Northwestern India. However, most people worldwide remain lactase non-persistent.^[9] Populations that raised animals not used for milk tend to have 90–100 percent of a lactose intolerant rate.^[78] For this reason, lactase persistence is of some interest to the fields of anthropology, human genetics, and archaeology, which typically use the genetically derived persistence/non-persistence terminology.^[79]

The rise of dairy and producing dairy related products from cow milk alone, varies across different regions of the world, aside from genetic predisposition.^[45] The process of turning milk into cheese dates back earlier than 5200 BC.^[80]

DNA analysis in February 2012 revealed that Ötzi was lactose intolerant, supporting the theory that lactose intolerance was still common at that time, despite the increasing spread of agriculture and dairying.^[81]

Genetic analysis shows lactase persistence has developed several times in different places independently in an example of convergent evolution.^[25]

History of research

It was not until relatively recently that

Most mammals normally cease to produce lactase and become lactose intolerant after weaning.^[9] The downregulation of lactase expression in mice could be attributed to the accumulation of DNA methylation in the Lct gene and the adjacent Mcm6 gene.^[95]

See also

References