Editing Lactose intolerance (section)

==Causes==
Lactose intolerance is a consequence of [[lactase]] deficiency, which may be genetic ([[#Primary hypolactasia|primary hypolactasia]] and [[#Primary congenital alactasia|primary congenital alactasia]]) or environmentally induced ([[#Secondary hypolactasia|secondary or acquired hypolactasia]]). In either case, symptoms are caused by insufficient levels of lactase in the lining of the [[duodenum]]. Lactose, a [[disaccharide]] molecule found in milk and dairy products, cannot be directly absorbed through the wall of the small intestine into the bloodstream, so, in the absence of lactase, passes intact into the [[Colon (anatomy)|colon]].{{Citation needed|reason=nutrients take 7-9 hours to reach colon but symptoms appear after 2 hours|date=January 2019}} [[Gut flora|Bacteria]] in the colon can metabolise lactose, and the resulting [[fermentation (biochemistry)|fermentation]] produces copious amounts of gas (a mixture of [[hydrogen]], [[carbon dioxide]], and [[methane]]) that causes the various abdominal symptoms. The unabsorbed sugars and fermentation products also raise the [[osmotic pressure]] of the colon, causing an increased flow of water into the bowels (diarrhea).<ref name="eMedicine overview">{{EMedicine|article|187249|Lactose intolerance|overview}}</ref><ref name="Genetics of lactase persistence and">{{cite journal | vauthors = Swallow DM | title = Genetics of lactase persistence and lactose intolerance | journal = Annual Review of Genetics | volume = 37 | pages = 197–219 | year = 2003 | pmid = 14616060 | doi = 10.1146/annurev.genet.37.110801.143820 }}</ref>

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.<ref name="medlineplus.gov">{{Cite web |title=Lactose intolerance: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/lactose-intolerance/ |access-date=2022-03-22 |website=medlineplus.gov |language=en}}</ref> 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.<ref>{{cite web|url=http://ghr.nlm.nih.gov/gene/MCM6|title=MCM6|author=Genetics Home Reference|website=Genetics Home Reference|url-status=live|archive-url=https://web.archive.org/web/20131004212751/http://ghr.nlm.nih.gov/gene/MCM6|archive-date=2013-10-04}}</ref> 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.<ref name="slate.com">{{cite web|url=http://www.slate.com/articles/health_and_science/human_evolution/2012/10/evolution_of_lactose_tolerance_why_do_humans_keep_drinking_milk.html|title=Evolution of lactose tolerance: Why do humans keep drinking milk?|author=Benjamin Phelan|date=23 October 2012|website=Slate Magazine|url-status=live|archive-url=https://web.archive.org/web/20130831021427/http://www.slate.com/articles/health_and_science/human_evolution/2012/10/evolution_of_lactose_tolerance_why_do_humans_keep_drinking_milk.html|archive-date=31 August 2013}}</ref> 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.<ref name="slate.com"/> 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." According to Johns Hopkins Medicine, lactose intolerance is more common in Asian Americans, African Americans, Mexican Americans, and Native Americans.<ref>{{cite web|title=Lactose Intolerance|url=http://www.hopkinsmedicine.org/healthlibrary/conditions/digestive_disorders/lactose_intolerance_85,P00388/|publisher=Johns Hopkins Health Library|access-date=2014-02-18|url-status=live|archive-url=https://web.archive.org/web/20140226235255/http://www.hopkinsmedicine.org/healthlibrary/conditions/digestive_disorders/lactose_intolerance_85,P00388/|archive-date=2014-02-26}}</ref> 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.<ref>{{cite journal |first=Ann |last=Gibbons |title=How Europeans evolved white skin |date=2 April 2015 |journal=Science |url=https://www.science.org/content/article/how-europeans-evolved-white-skin |doi=10.1126/science.aab2435}}</ref>

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.<ref>{{cite journal | vauthors = Beja-Pereira A, Luikart G, England PR, Bradley DG, Jann OC, Bertorelle G, Chamberlain AT, Nunes TP, Metodiev S, Ferrand N, Erhardt G | s2cid = 20415396 | title = Gene-culture coevolution between cattle milk protein genes and human lactase genes | journal = Nature Genetics | volume = 35 | issue = 4 | pages = 311–3 | date = December 2003 | pmid = 14634648 | doi = 10.1038/ng1263 }}</ref> 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.<ref name="Lactose digestion and the evolution"/> 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 people|Beja]] pastoralist population in [[Sudan]].<ref name=Tishkoff07/>

The accumulation of [[Epigenetics|epigenetic]] factors, primarily [[DNA methylation]], in the extended LCT region, including the gene [[Enhancer (genetics)|enhancer]] located in the ''MCM6'' gene near C/T-13910 SNP, may also contribute to the onset of lactose intolerance in adults.<ref>{{cite journal | vauthors = Labrie V, Buske OJ, Oh E, Jeremian R, Ptak C, Gasiūnas G, Maleckas A, Petereit R, Žvirbliene A, Adamonis K, Kriukienė E, Koncevičius K, Gordevičius J, Nair A, Zhang A, Ebrahimi S, Oh G, Šikšnys V, Kupčinskas L, Brudno M, Petronis A | title = Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging | journal = Nature Structural & Molecular Biology | volume = 23 | issue = 6 | pages = 566–73 | date = June 2016 | pmid = 27159559 | pmc = 4899171 | doi = 10.1038/nsmb.3227 }}</ref><ref name=Oh17>{{Cite journal|last1=Oh|first1=Edward|last2=Jeremian|first2=Richie|last3=Oh|first3=Gabriel|last4=Groot|first4=Daniel|last5=Susic|first5=Miki|last6=Lee|first6=KwangHo|last7=Foy|first7=Kelly|last8=Laird|first8=Peter W.|last9=Petronis|first9=Arturas|last10=Labrie|first10=Viviane|date=2017-01-31|title=Transcriptional heterogeneity in the lactase gene within cell-type is linked to the epigenome|journal=Scientific Reports|volume=7|issue=1|page=41843|doi=10.1038/srep41843|pmid=28139744|pmc=5282553|bibcode=2017NatSR...741843O |doi-access=free}}</ref> Age-dependent expression of ''LCT'' in mice intestinal epithelium has been linked to DNA methylation in the gene enhancer.<ref name=Oh17 />

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.<ref name="Heyman2006" /><ref name=variant>{{cite journal | vauthors = Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I | s2cid = 21430931 | title = Identification of a variant associated with adult-type hypolactasia | journal = Nature Genetics | volume = 30 | issue = 2 | pages = 233–7 | date = February 2002 | pmid = 11788828 | doi = 10.1038/ng826 }}</ref> 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 [[Pastoralism|pastoralist]] populations from Africa.<ref name="Genetics of lactase persistence and"/>
; Secondary hypolactasia
: Secondary hypolactasia or secondary lactase deficiency, also called acquired hypolactasia or acquired lactase deficiency, is caused by an injury to the [[small intestine]]. This form of lactose intolerance can occur in both infants and lactase persistent adults and is generally reversible.<ref>{{cite web|title=Lactose intolerance|url=http://www.milk.co.uk/page.aspx?intPageID=59|url-status=dead|archive-url=https://web.archive.org/web/20160309024816/http://www.milk.co.uk/page.aspx?intPageID=59|archive-date=9 March 2016|website=The Dairy Council UK}}</ref> It may be caused by acute [[gastroenteritis]], [[coeliac disease]], [[Crohn's disease]], [[ulcerative colitis]],<ref>[http://www.nhs.uk/Conditions/lactose-intolerance/Pages/Causes.aspx Secondary lactase deficiency causes] {{webarchive|url=https://web.archive.org/web/20160731180402/http://www.nhs.uk/Conditions/lactose-intolerance/Pages/Causes.aspx |date=2016-07-31 }}</ref> [[chemotherapy]], [[intestinal parasites]] (such as [[giardia]]), or other environmental causes.<ref name="Heyman2006" /><ref>{{cite book |last1=Lawson |first1=Margaret |last2=Bentley |first2=Donald |last3=Lifschitz |first3=Carlos | title=Pediatric gastroenterology and clinical nutrition |year=2002 |publisher=Remedica |location=London |isbn=978-1-901346-43-5 |url=https://books.google.com/books?id=dLLgzcMsbo0C&pg=PA109 |page=109 |url-status=live |archive-url=https://web.archive.org/web/20161219183419/https://books.google.com/books?id=dLLgzcMsbo0C&pg=PA109 |archive-date=2016-12-19}}</ref><ref name="eMedicine pediatric">{{Emedicine|emerg|930971|Pediatric Lactose Intolerance}}</ref><ref name=SwagertyWalling2002>{{cite journal | vauthors = Swagerty DL, Walling AD, Klein RM | title = Lactose intolerance | journal = American Family Physician | volume = 65 | issue = 9 | pages = 1845–50 | date = May 2002 | pmid = 12018807 | url = http://www.aafp.org/link_out?pmid=12018807 }}</ref>
; 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.<ref name="Heyman2006" /> 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,<ref name="Heyman2006" /> but death rates decreased with [[soybean]]-derived [[infant formula]]s and manufactured lactose-free dairy products.<ref name="Sinden_1991">{{cite journal | vauthors = Sinden AA, Sutphen JL | title = Dietary treatment of lactose intolerance in infants and children | journal = Journal of the American Dietetic Association | volume = 91 | issue = 12 | pages = 1567–71 | date = December 1991 | doi = 10.1016/S0002-8223(21)01435-8 | pmid = 1960350 | s2cid = 32296893 }}</ref>