Editing Kwashiorkor (section)

== Causes ==
The precise etiology of kwashiorkor remains unclear.<ref name=":1">{{Cite web|url=https://www.ennonline.net/attachments/2314/Kwashiorkor-still-an-enigma-CMAM-Forum-Dec-2014.pdf|title=Kwashiorkor: still an enigma – the search must go on|last=Briend|first=Andre|name-list-style=vanc|date=2014|website=Emergency Nutrition Network|access-date=2 August 2019|archive-date=15 February 2022|archive-url=https://web.archive.org/web/20220215095457/https://www.ennonline.net/attachments/2314/Kwashiorkor-still-an-enigma-CMAM-Forum-Dec-2014.pdf|url-status=live}}</ref><ref name="G. Coulthard 2015"/><ref name="Smith Yatsunenko Manary 2013">{{cite journal |last1=Smith |first1=Michelle I. |last2=Yatsunenko |first2=Tanya |last3=Manary |first3=Mark J. |last4=Trehan |first4=Indi |last5=Mkakosya |first5=Rajhab |last6=Cheng |first6=Jiye |last7=Kau |first7=Andrew L. |last8=Rich |first8=Stephen S. |last9=Concannon |first9=Patrick |last10=Mychaleckyj |first10=Josyf C. |last11=Liu |first11=Jie |last12=Houpt |first12=Eric |last13=Li |first13=Jia V. |last14=Holmes |first14=Elaine |last15=Nicholson |first15=Jeremy |last16=Knights |first16=Dan |last17=Ursell |first17=Luke K. |last18=Knight |first18=Rob |last19=Gordon |first19=Jeffrey I. |title=Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor |journal=Science |date=February 2013 |volume=339 |issue=6119 |pages=548–554 |doi=10.1126/science.1229000 |pmid=23363771 |pmc=3667500 |bibcode=2013Sci...339..548S }}</ref> Several hypotheses have been proposed that are associated with and explain some, but not all aspects of the pathophysiology of kwashiorkor. They include, but are not limited to protein deficiency causing hypoalbuminemia, amino acid deficiency, oxidative stress, and gut microbiome changes.<ref name=":1" /><ref name="Smith Yatsunenko Manary 2013"/><ref>{{cite journal|vauthors=Velly H, Britton RA, Preidis GA|date=2017|title=Mechanisms of cross-talk between the diet, the intestinal microbiome, and the undernourished host|journal=Gut Microbes|volume=8|issue=2|pages=98–112|doi=10.1080/19490976.2016.1267888|pmc=5390823|pmid=27918230}}</ref>

=== Low protein intake ===
[[File:Protein-energy malnutrition world map - DALY - WHO2002.svg|thumb|upright=1.2|[[Disability-adjusted life year]]s per 100,000&nbsp;inhabitants for protein-energy malnutrition in 2002:<ref>{{cite web |url=https://www.who.int/entity/healthinfo/statistics/bodgbddeathdalyestimates.xls |title=Mortality and Burden of Disease Estimates for WHO Member States in 2002 |format=xls |work=World Health Organization |year=2002 |access-date=5 October 2020 |archive-date=16 January 2013 |archive-url=https://web.archive.org/web/20130116174540/http://www.who.int/healthinfo/statistics/bodgbddeathdalyestimates.xls |url-status=live }}</ref>{{Div col|small=yes|colwidth=10em}}
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|fewer than 10}}
{{legend|#fff200|10–100}}
{{legend|#ffdc00|100–200}}
{{legend|#ffc600|200–300}}
{{legend|#ffb000|300–400}}
{{legend|#ff9a00|400–500}}
{{legend|#ff8400|500–600}}
{{legend|#ff6e00|600–700}}
{{legend|#ff5800|700–800}}
{{legend|#ff4200|800–1000}}
{{legend|#ff2c00|1000–1350}}
{{legend|#cb0000|more than 1350}}
{{div col end}}]]
Kwashiorkor is a severe form of [[malnutrition]] associated with a low-protein diet.<ref name="Benjamin & Lappin Kwashiorkor"/> The extreme lack of protein causes an osmotic imbalance in the [[Human gastrointestinal tract|gastrointestinal system]] causing swelling of the gut diagnosed as an [[edema]] or retention of water.<ref name="williams1935" />

Extreme fluid retention observed in individuals suffering from kwashiorkor is accompanied by irregularities in the [[lymphatic system]] as well as disruptions of capillary exchange. The lymphatic system serves three major purposes: fluid recovery, immunity, and [[lipid]] absorption. Victims of kwashiorkor commonly exhibit reduced ability to recover fluids, immune system failure, and low lipid absorption. Fluid recovery by the lymphatic system is accomplished by the re-vascularization of fluid and macromolecules from the interstitial space, allowing these constituents of whole blood to be returned to the venous circulation. Compromised fluid recovery may contribute to the phenomenon of extravascular fluid accumulation in kwashiorkor.<ref>{{cite journal | year = 1950 | title =  Nova et Vetera| journal = The British Medical Journal | volume = 2 | issue = 4673| page = 284 | doi = 10.1136/bmj.2.4673.267 | s2cid = 220181068}}</ref>

The low protein theory for the pathogenesis of kwashiorkor has been used to teach that capillary exchange between the lymphatic system and circulating blood is impaired by a reduced oncotic (i.e. colloid osmotic pressure, COP) in the blood, as a consequence of inadequate protein intake, so that the hydrostatic pressure gradient, which favors extravasation of fluid from small vessels, is not overcome. Proteins, mainly albumin, are responsible for creating the COP observed in the blood and tissue fluids. The difference in the COP of the blood and tissue tends to favor the reentry of fluid from the extravascular space, into the circulatory system. This tendency is opposed by the venous hydrostatic pressure, which tends to favor the exit of fluid from small vessels, into the interstitial space. The low protein theory for the pathogenesis of kwashiorkor held that a deficiency of serum proteins, caused by inadequate protein intake, disrupted this balance, and thus impaired the return flow of fluid from the interstitium into the capillary and venous structures. It has been taught that this is what accounts for the accumulation of extravascular fluid in kwashiorkor, and the subsequent pedal edema and abdominal distension.<ref>{{cite book |last=Saladin |first=Kenneth | name-list-style = vanc |title=Anatomy and Physiology |edition=6th |location=New York |publisher=McGraw Hill |year=2012 |pages=766–767, 809–811 |isbn=978-0-07-337825-1 }}</ref>

The low protein theory, which relies heavily upon Starling's theory for the movement of fluid in biological systems, provided a compelling rationale for the pathogenesis of edema in kwashiorkor. What it does not explain, however, is the entire array of disturbances that define the kwashiorkor syndrome. These include irritability, anorexia, skin desquamation, skin depigmentation, hair discoloration, reduced mitochondrial respiration, impaired lipid export from the liver without an accompanying reduction of lipoprotein synthesis, 'oxidative stress', glutathione depletions, [[transsulfuration]] disturbances, diffuse DNA hypomethylation, immune dysfunction, decreased transmethylation activity, and sulfated [[glycosaminoglycan]] deficiencies. It is now generally acknowledged that by itself, the low protein theory does not adequately account for the pathogenesis of kwashiorkor. More complex deficiencies are at work. These have still not been established. <ref>{{cite journal|vauthors=Tierney EP, Sage RJ, Shwayder T|date=2010|title=Kwashiorkor from a severe dietary restriction in an 8-month infant in suburban Detroit, Michigan: case report and review of the literature|journal=International Journal of Dermatology|volume=49|issue=5|pages=500–6|doi=10.1111/j.1365-4632.2010.04253.x|pmid=20534082|s2cid=13050691}}</ref>

Social factors are also relevant. Ignorance of nutrition can be a cause. A case was described where parents who fed their child [[cassava]] failed to recognize malnutrition because of the edema caused by the syndrome and believed the child was well-nourished despite the development of kwashiorkor.<ref>{{cite web|title=Malnutrition in Third World Countries|url=http://www.religion-online.org/showarticle.asp?title=1405.|website=www.religion-online.org|access-date=2 March 2017|archive-url=https://web.archive.org/web/20150919024954/http://www.religion-online.org/showarticle.asp?title=1405.|archive-date=19 September 2015|url-status=dead}}</ref>

=== Aflatoxins ===
Recent studies have attempted to pinpoint a relationship between kwashiorkor and high levels of [[aflatoxin]]s. Aflatoxins are naturally occurring toxins produced by the mold ''[[Aspergillus flavus]]'', a fungus found in areas with hot and humid climates.<ref name="Kumar Mahato Kamle et al 2017">{{cite journal |last1=Kumar |first1=Pradeep |last2=Mahato |first2=Dipendra K. |last3=Kamle |first3=Madhu |last4=Mohanta |first4=Tapan K. |last5=Kang |first5=Sang G. |title=Aflatoxins: A Global Concern for Food Safety, Human Health and Their Management |journal=Frontiers in Microbiology |date=17 January 2017 |volume=07 |page=2170 |doi=10.3389/fmicb.2016.02170 |pmid=28144235 |pmc=5240007 |doi-access=free }}</ref> These toxins tend to grow and can be found in agricultural crops such as millet, maize, and rice.<ref name="Kumar Mahato Kamle et al 2017"/> An analysis found that the presence of aflatoxins was found more frequently and in higher concentrations in individuals with kwashiorkor when compared to individuals with marasmus (another form of severe acute malnutrition).<ref name="Soriano Rubini Morales-Suarez-Varela et al 2020">{{cite journal |last1=Soriano |first1=Jose M. |last2=Rubini |first2=Ana |last3=Morales-Suarez-Varela |first3=María |last4=Merino-Torres |first4=Juan F. |last5=Silvestre |first5=Dolores |title=Aflatoxins in organs and biological samples from children affected by kwashiorkor, marasmus and marasmic-kwashiorkor: A scoping review |journal=Toxicon |date=October 2020 |volume=185 |pages=174–183 |doi=10.1016/j.toxicon.2020.07.010 |pmid=32693007 |bibcode=2020Txcn..185..174S |s2cid=220698925 }}</ref><ref>{{cite journal |last1=Watson |first1=Sinead |last2=Gong |first2=Yun Yun |last3=Routledge |first3=Michael |title=Interventions Targeting Child Undernutrition in Developing Countries May Be Undermined by Dietary Exposure to Aflatoxin |journal=Critical Reviews in Food Science and Nutrition |date=15 July 2015 |volume=57 |issue=9 |pages=1963–1975 |doi=10.1080/10408398.2015.1040869 |pmid=26176888 |s2cid=24089209 |url=http://eprints.whiterose.ac.uk/124824/3/Interventions%20targeting%20child%20undernutrition%20in%20developing%20countries%20may%20be%20undermined%20by%20dietary%20exposure%20to%20aflatoxin%207th%20JAN%20SW%20%282%29.pdf }}</ref> In particular, biological samples showed greater levels of aflatoxins in the brain, heart, kidney, liver, lungs, serum, stool, and urine.<ref name="Soriano Rubini Morales-Suarez-Varela et al 2020"/> Aflatoxins were not found in liver samples of individuals with marasmus.<ref name="Soriano Rubini Morales-Suarez-Varela et al 2020"/> It has been known that the liver organ is the main target of aflatoxins and chronic toxicity can result in immunosuppressive and carcinogenic effects.<ref name="Soriano Rubini Morales-Suarez-Varela et al 2020"/> However, there is currently conflicting evidence to pinpoint a connection between kwashiorkor and aflatoxins. Studies have shown that not all children with kwashiorkor present with detectable aflatoxin levels.<ref name="Pham Alou Golden et al 2021"/> It has also been proposed that damage done by aflatoxins may be due to glutathione depletion (another proposed mechanism of the disease) in children with kwashiorkor.<ref name="Pham Alou Golden et al 2021"/>