View source for Pellagra

{{Short description|Human disease caused by a lack of vitamin B3}}
{{Use dmy dates|date=July 2023}}
{{Infobox medical condition (new)
| name            = Pellagra
| image           = Pellagra2.jpg
| caption         = The skin features of pellagra including [[desquamation|peeling]], [[erythema|redness]], scaling, and [[keratosis|thickening]] of sun-exposed areas.
| field           = [[Dermatology]]
| symptoms        = [[Dermatitis|Inflammation of the skin]], [[diarrhea]], [[dementia]], sores in the mouth<ref name=Ng2003/>
| complications   =
| onset           =
| duration        =
| types           = Primary, secondary<ref name=Ng2003/>
| causes          = Not enough [[Niacin (substance)|niacin]]<ref name=Or2017/>
| risks           =
| diagnosis       = Based on symptoms<ref name=Pit2005/>
| differential    = [[Kwashiorkor]], [[pemphigus]], [[photodermatitis]], [[porphyria]]<ref name=Pit2005/>
| prevention      = Consuming Niacin
| treatment       = [[Nicotinic acid]] or [[nicotinamide]] supplementation.<ref name=Ng2003/>
| medication      =
| prognosis       = Good (with treatment), death in ~ 5 years (without treatment)<ref name=Pit2005/>
| frequency       = Rare (developed world), relatively common (developing world)<ref name=Pit2005/>
| deaths          =
}}
<!-- Definition and symptoms -->

'''Pellagra'''  is a [[disease]] caused by a lack of the vitamin [[Niacin (substance)|niacin]] (vitamin B<sub>3</sub>).<ref name=Or2017>{{cite web|title=Orphanet: Pellagra|url=http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97352|website=orpha.net|access-date=10 June 2017|language=en|url-status=live|archive-url=https://web.archive.org/web/20170417155540/http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN|archive-date=17 April 2017}}</ref> Symptoms include [[dermatitis|inflamed skin]], [[diarrhea]], [[dementia]], and sores in the mouth.<ref name=Ng2003/> Areas of the skin exposed to friction and radiation are typically affected first.<ref name=Ng2003/> Over time affected skin may become darker, stiffen, peel, or bleed.<ref name=Ng2003/><ref name=Pit2005/>

<!-- Cause and diagnosis -->
There are two main types of pellagra, primary and secondary.<ref name=Ng2003/> Primary pellagra is due to a diet that does not contain enough niacin and [[tryptophan]].<ref name=Ng2003/> Secondary pellagra is due to a poor ability to use the niacin within the diet.<ref name=Ng2003/> This can occur as a result of [[alcoholism]], long-term diarrhea, [[carcinoid syndrome]], [[Hartnup disease]], and a number of medications such as [[isoniazid]].<ref name=Ng2003/> Diagnosis is typically based on symptoms and may be assisted by urine testing.<ref name=Pit2005/>

<!-- Prevention and treatment -->
Treatment is with either [[nicotinic acid]] or [[nicotinamide]] supplementation.<ref name=Ng2003/> Improvements typically begin within a couple of days.<ref name=Ng2003/> General improvements in diet are also frequently recommended.<ref name=Pit2005/> Decreasing sun exposure via [[sunscreen]] and proper clothing is important while the skin heals.<ref name=Ng2003>{{cite web|last1=Ngan|first1=Vanessa|title=Pellagra|url=http://www.dermnetnz.org/topics/pellagra/|website=DermNet New Zealand|access-date=10 June 2017|language=en|year=2003|url-status=live|archive-url=https://web.archive.org/web/20170409053629/http://www.dermnetnz.org/topics/pellagra/|archive-date=9 April 2017}}</ref> Without treatment death may occur.<ref name=Pit2005/> The disease occurs most commonly in the [[developing world]], often as a [[disease of poverty]] associated with [[malnutrition]], specifically [[sub-Saharan Africa]].<ref name=Pit2005>{{cite journal |last= Pitche |first= P. |date= 2005 |title= Pellagra |journal= Santé |volume= 15 |issue= 3 |pages= 205–08 |pmid= 16207585}}</ref>

==Etymology==
The word ''{{linktext|pellagra}}'' is known to come from [[Lombardic language|Lombardic]], but its exact origins are disputed. "Pell" certainly arises from classical Latin {{lang|la|pellis}}, meaning "skin".<ref name=Lombard>{{cite book|first=Francesco|last=Cherubini|title=Vocabolario Milanese-Italiano|language=it,lmo|publisher=Imp. Regia Stamperia|year=1840–1843|volume=I. III}}</ref><ref name=OED>{{cite OED|pellagra ''n''.|1005242239}}</ref> "-agra" may arise from Lombardic {{lang|lmo|agra}}, meaning "like [[Serous fluid|serum]] or [[holly]] juice",<ref name=Lombard /> or the Latinate {{lang|la|-agra}},<ref name=OED /> a suffix for maladies itself borrowed from the Greek {{lang|el|ἄγρα}}, meaning "a catch-point, a hunting trap".<ref>{{cite OED|podagra ''n.''|1000750596}}</ref>

== Signs and symptoms ==
[[File:PHIL 3757 lores.jpg|thumb|This child has the [[casal collar]] skin rash around the neck associated with pellagra.]]
[[File:Pellagra NIH.jpg|thumb|Man with pellagra with typical [[skin lesion]]s]]
The classic symptoms of pellagra are [[diarrhea]], [[dermatitis]], [[dementia]], and death ("the four Ds").<ref name="Hegyi2004">{{cite journal |last1= Hegyi |first1= J. |last2= Schwartz |first2= R. A. |last3= Hegyi |first3= V. |date= 2004 |title= Pellagra: Dermatitis, dementia, and diarrhea |journal= International Journal of Dermatology |volume= 43 |pages= 1–5 |issue= 1 |pmid= 14693013 |s2cid= 33877664 |doi= 10.1111/j.1365-4632.2004.01959.x |doi-access= free }}</ref>

A more comprehensive list of symptoms includes:
* [[Dermatitis]] (characteristic "broad collar" rash known as [[casal collar]])
* [[Alopecia|Hair loss]]
* [[Edema|Swelling]]
* Smooth, beefy red [[glossitis]] (tongue inflammation)
* [[Insomnia|Trouble sleeping]]
* [[Weakness]]
* [[Mental confusion]] or [[aggression]]
* [[Ataxia]] (lack of coordination), paralysis of extremities, [[peripheral neuritis]] (nerve damage)
* [[Diarrhea]]
* [[Dilated cardiomyopathy]] (enlarged, weakened heart)
* [[Photodermatitis|Sensitivity to radiation]]
* Eventually [[dementia]]

J. Frostigs and [[Tom Spies]]—according to Cleary and Cleary<ref name= accCnC/>—described more specific psychological symptoms of pellagra as:
* Psychosensory disturbances (impressions as being painful, annoying bright lights, odors intolerance causing nausea and vomiting, dizziness after sudden movements),
* Psychomotor disturbances (restlessness, tense and a desire to quarrel, increased preparedness for motor action), as well as
* Emotional disturbances<ref name= accCnC >{{cite journal |last1= Cleary |first1= M. J. |last2= Cleary |first2= J. P. |date= 1989 |title= Anorexia nervosa: a form of subclinical pellagra |journal= Int Clin Nutr Rev |volume= 9 |issue= 3 |pages= 137–43 |issn= 0813-9008 }}</ref><ref>{{cite journal |last1= Frostig |first1= J. P. |last2= Spies |first2= T. D. |date= 1940 |title= The initial syndrome of pellagra and associated deficiency diseases |journal= American Journal of the Medical Sciences |volume= 199 |issue= 268 |doi= 10.1097/00000441-194002000-00016 }}</ref>

Independently of clinical symptoms, blood level of tryptophan or urinary metabolites such as [[2-pyridone]]/[[N-methylnicotinamide]] ratio <2 or [[Nicotinamide adenine dinucleotide|NAD]]/[[Nicotinamide adenine dinucleotide phosphate|NADP]] ratio in [[erythrocyte|red blood cells]] can diagnose pellagra. The diagnosis is confirmed by rapid improvements in symptoms after doses of nicotinamide (250–500&nbsp;mg/day) or nicotinamide enriched food.<ref>{{cite journal |last1= Gehring |first1= W. |date= 2004 |title= Nicotinic acid/niacinamide and the skin |journal= Journal of Cosmetic Dermatology |volume= 3 |issue= 2 |pages= 88–93 |pmid= 17147561 |s2cid= 38510987 |doi= 10.1111/j.1473-2130.2004.00115.x }}</ref>

== Pathophysiology ==
Pellagra can develop according to several mechanisms, classically as a result of niacin (vitamin B3) deficiency, which results in decreased [[nicotinamide adenine dinucleotide]] (NAD). Since NAD and its phosphorylated NADP form are cofactors required in many body processes, the pathological impact of pellagra is broad and results in death if not treated.

The first mechanism is simple dietary lack of niacin. Second, it may result from deficiency of [[tryptophan]],<ref name=Pit2005/> an [[essential amino acid]] found in meat, poultry, fish, eggs, and [[peanut]]s,<ref>{{cite web |last= Haas |first= Elson M. |date= n.d. |title= Vitamin B3 – Niacin |work= Excepted from: Staying Healthy with Nutrition: The Complete Guide to Diet and Nutritional Medicine |url= http://www.healthy.net/scr/article.asp?ID=2125 |access-date= 18 June 2007 |url-status= dead |archive-url= https://web.archive.org/web/20070323014227/http://www.healthy.net/scr/article.asp?ID=2125 |archive-date= 23 March 2007 }}</ref> which the body [[Niacin (substance)#Production|uses to make niacin]]. Third, it may be caused by excess [[leucine]], as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of nicotinic acid to nicotinamide mononucleotide (NMN) causing pellagra-like symptoms to occur.<ref name=Bapurao_1978>{{cite journal |last1= Bapurao |first1= S. |last2= Krishnaswamy |first2= K. |date= 1978 |title= Vitamin B6 nutritional status of pellagrins and their leucine tolerance |journal= Am J Clin Nutr |volume= 31 |issue= 5 |pages= 819–24 |pmid= 206127 |doi= 10.1093/ajcn/31.5.819 |doi-access= free }}</ref>

Some conditions can prevent the absorption of dietary niacin or tryptophan and lead to pellagra. Inflammation of the [[jejunum]] or [[ileum]] can prevent nutrient absorption, leading to pellagra, and this can in turn be caused by [[Crohn's disease]].<ref name=whoprinzo24>{{cite report |author= ((World Health Organization)) |date= 2000 |title= Pellagra And Its Prevention And Control in Major Emergencies |author-link= World Health Organization |hdl= 10665/66704 |hdl-access= free |id= WHO/NHD/00.10}}</ref> [[Gastroenterostomy]] can also cause pellagra.<ref name=whoprinzo24 /> Chronic [[alcoholism]] can also cause poor absorption, which combined with a diet already low in niacin and tryptophan produces pellagra.<ref name=whoprinzo24 /> [[Hartnup disease]] is a genetic disorder that reduces tryptophan absorption, leading to pellagra.

Alterations in protein metabolism may also produce pellagra-like symptoms. An example is [[carcinoid syndrome]], a disease in which neuroendocrine tumors along the GI tract use tryptophan as the source for [[serotonin]] production, which limits the available tryptophan for niacin synthesis. In normal patients, only one percent of dietary tryptophan is converted to serotonin; however, in patients with carcinoid syndrome, this value may increase to 70%.  Carcinoid syndrome thus may produce niacin deficiency and clinical manifestations of pellagra.  Anti-tuberculosis medication tends to bind to vitamin B<sub>6</sub> and reduce niacin synthesis, since B<sub>6</sub> (pyridoxine) is a required cofactor in the tryptophan-to-niacin reaction.

Several therapeutic drugs can provoke pellagra. These include the antibiotics [[isoniazid]], which decreases available B<sub>6</sub> by binding to it and making it inactive, so it cannot be used in niacin synthesis,<ref>{{cite web |last= Chhrabra |first= Namrata |date= 2014-01-18 |title= Case study – Pellagra |website= Biochemistry for Medics – Clinical Cases |url= http://usmle.biochemistryformedics.com/answer-case-study-pellagra-a-56-year-old-male-on-isoniazid-therapy-for-tuberculosis/ |url-status= dead |archive-url= https://web.archive.org/web/20150518082416/http://usmle.biochemistryformedics.com/answer-case-study-pellagra-a-56-year-old-male-on-isoniazid-therapy-for-tuberculosis/ |archive-date= 18 May 2015 }}</ref> and [[chloramphenicol]]; the anti-cancer agent [[fluorouracil]]; and the [[immunosuppressant]] [[mercaptopurine]].<ref name=whoprinzo24 />

== Treatment ==
If untreated, pellagra can kill within four or five years.<ref name="Pit2005" /> Treatment is with [[nicotinamide]], which has the same vitamin function as nicotinic acid and a similar chemical structure, but has lower toxicity. The frequency and amount of nicotinamide administered depends on the degree to which the condition has progressed.<ref name=WHO2008>{{cite book |author= ((World Health Organization)) |date= 2009 |title= WHO Model Formulary 2008 |isbn= 9789241547659 |editor-last1= Stuart |editor-first1= M. C. |editor-last2= Kouimtzi |editor-first2= M. |editor-last3= Hill |editor-first3= S. R. |pages= 496, 500 |hdl= 10665/44053 |author-link= World Health Organization |hdl-access= free }}</ref>

== Epidemiology ==
[[File:A girl in the London Asylum suffering from chronic pellagra. Wellcome V0022633.jpg|thumb|A girl in the London Asylum in 1925]]
Pellagra can be common in people who obtain most of their [[food energy]] from [[maize|corn]], notably rural [[South America]], where maize is a [[staple food]]. If maize is not [[Nixtamalization|nixtamalized]], it is a [[Essential amino acid#Protein quality|poor source of tryptophan]], as well as niacin. Nixtamalization corrects the niacin deficiency, and is a common practice in [[Indigenous people of the Americas|Native American]] cultures that grow corn, but most especially in [[Mexico]] and the countries of [[Central America]]. Following the corn cycle, the symptoms usually appear during spring, increase in the summer due to greater sun exposure, and return the following spring. Indeed, pellagra was once [[endemic (epidemiology)|endemic]] in the poorer states of the U.S. South, such as Mississippi and Alabama, where its cyclical appearance in the spring after meat-heavy winter diets led to it being known as "spring sickness" (particularly when it appeared among more vulnerable children), as well as among the residents of jails and orphanages as studied by Dr. [[Joseph Goldberger]].<ref>{{cite book|last=Spark|first=Arlene|title=Nutrition in Public Health: Principles, Policies, and Practice|url=https://books.google.com/books?id=zgYREbEYpfwC&pg=PA79|year=2007|publisher=CRC Press|isbn=978-0-203-50788-9|page=79|url-status=live|archive-url=https://web.archive.org/web/20170414231642/https://books.google.com/books?id=zgYREbEYpfwC&pg=PA79|archive-date=14 April 2017}}</ref>

Pellagra is common in Africa, Indonesia, and China. In affluent societies, a majority of patients with clinical pellagra are poor, homeless, alcohol-dependent, or psychiatric patients who refuse food.<ref name="pmid17712518">{{cite journal |last1= Jagielska |first1= G. |last2= Tomaszewicz-Libudzic |first2= E. C. |last3= Brzozowska |first3= A. |date= 2007 |title= Pellagra: a rare complication of anorexia nervosa |journal= Eur Child Adolesc Psychiatry |volume= 16 |issue= 7 |pages= 417–20 |pmid= 17712518 |s2cid= 249366 |doi= 10.1007/s00787-007-0613-4}}</ref> Pellagra was common among prisoners of Soviet labor camps (the [[Gulag]]s).  In addition, pellagra, as a micronutrient deficiency disease, frequently affects populations of refugees and other displaced people due to their unique, long-term residential circumstances and dependence on [[food aid]]. Refugees typically rely on limited sources of vitamin B<sub>3</sub> provided to them, often [[peanut]]s (which, in Africa, may be supplied in place of local groundnut staples, such as the [[Bambara groundnut|Bambara]] or [[Hausa groundnut]]); the instability in the nutritional content and distribution of food aid can be the cause of pellagra in displaced populations. In the 2000s, there were outbreaks in countries such as Angola, Zimbabwe and Nepal.<ref>{{cite journal |doi=10.1016/S0140-6736(05)73093-2 |pmid=10832866 |title=Pellagra outbreak in Kuito, Angola |year=2000 |last1=Baquet |first1=S. |last2=Wuillaume |first2=F. |last3= van Egmond |first3=K. |last4=Ibañez |first4=F. |s2cid=40916536 |journal=The Lancet |volume=355 |issue=9217 |pages=1829–30}}</ref><ref>{{cite journal |last1= Dhakak |first1= M. |last2= Limbu |first2= B. |last3= Neopane |first3= A. |last4= Karki |first4= D. B. |date= 2003 |title= A typical case of pellagra |volume= 1 |issue= 1 |pages= 36–37 |journal= Kathmandu University Medical Journal |pmid= 16340260 }}</ref><ref name="Seal et al 2007">{{cite journal |last1= Seal |first1= A. J. |last2= Creeke |first2= P. I. |last3= Dibari |first3= F. |last4= Cheung |first4= E. |last5= Kyroussis |first5= E. |last6= Semedo |first6= P. |last7= van den Briel |first7= T. |date= 2007 |title= Low and deficient niacin status and pellagra are endemic in postwar Angola |volume= 85 |issue= 1 |pages= 218–24 |journal= The American Journal of Clinical Nutrition |pmid= 17209199 |doi= 10.1093/ajcn/85.1.218 |doi-access= free }}</ref> In Angola specifically, recent reports show a similar incidence of pellagra since 2002, with clinical pellagra in 0.3% of women and 0.2% of children and niacin deficiency in 29.4% of women and 6% of children related to high untreated corn consumption.<ref name="Seal et al 2007" />

In other countries such as the Netherlands and Denmark, even with sufficient intake of niacin, cases have been reported. In this case, deficiency might happen not just because of poverty or malnutrition but secondary to alcoholism, drug interaction ([[Psychoactive drug|psychotropic]], [[Cytostasis|cytostatic]], [[tuberculostatic]] or [[analgesic]]s), [[HIV]], [[Riboflavin|vitamin B<sub>2</sub>]] and [[Vitamin B6|B<sub>6</sub>]] deficiency, or malabsorption syndromes such as [[Hartnup disease]] and [[Carcinoid|carcinoid tumors]].<ref name="Seal et al 2007" /><ref name="Hegyi2004" /><ref>{{cite journal |last1= Monteiro |first1= J. P. |last2= da Cunha |first2= D. F. |last3= Filho |first3= D. C. |last4= Silva-Vergara |first4= M. L. |last5= dos Santos |first5= V. M. |last6= da Costa |first6= J. C. Jr |last7= Etchebehere |first7= R. M. |last8= Gonçalves |first8= J. |last9= de Carvalho da Cunha |first9= S. F. |date= 2004 |title= Niacin metabolite excretion in alcoholic pellagra and AIDS patients with and without diarrhea |journal= Nutrition |volume= 20 |issue= 9 |pages= 778–82 |pmid= 15325687 |doi= 10.1016/j.nut.2004.05.008 |display-authors= etal}}</ref><ref>{{cite journal |doi=10.1111/j.1346-8138.2010.01189.x |title=Azathioprine-induced pellagra |year=2011 |last1=Oliveira |first1=A. |last2=Sanches |first2=M. |last3=Selores |first3=M. | journal = The Journal of Dermatology |volume=38 |issue=10 |pages=1035–37 |pmid=21658113|s2cid=3396280 }}</ref><ref>{{cite journal |doi=10.1097/MJT.0b013e31815ae309 |title=Pellagra: Rekindling of an Old Flame |year=2008 |last1=Delgado-Sanchez |first1=L. |last2=Godkar |first2=D. |last3=Niranjan |first3=S. |s2cid=23889445 |journal=[[American Journal of Therapeutics]] |volume=15 |issue=2 |pages=173–75 |pmid=18356638}}</ref>

== History ==

[[Indigenous peoples of the Americas|Native American]] cultivators who first domesticated corn ([[maize]]) prepared it by [[nixtamalization]], in which the grain is treated with a solution of [[alkali]] such as [[calcium hydroxide|lime]]. Nixtamalization makes the niacin nutritionally available and prevents pellagra.<ref name="Rajakumar2000">{{cite journal |last1= Rajakumar |first1= Kumaravel |date= 2000 |title= Pellagra in the United States: A Historical Perspective |journal=Southern Medical Journal |volume= 93 |issue= 3 |pages= 272–277 |doi= 10.1097/00007611-200093030-00005 |issn= 0038-4348 |pmid= 10728513 |url= http://www.jmcgowan.com/pellagra.pdf |url-status= live |archive-url= https://web.archive.org/web/20150224002027/http://www.jmcgowan.com/pellagra.pdf|archive-date= 24 February 2015}}</ref> When maize was cultivated worldwide, and eaten as a staple without nixtamalization, pellagra became common.

Pellagra was first described for its dermatological effect in Spain in 1735 by [[Gaspar Casal]]. He explained that the disease causes dermatitis in exposed skin areas such as hands, feet and neck and that the origin of the disease is poor diet and atmospheric influences.<ref>{{cite book |last1= Casal |first1= G. |date= 1945 |chapter= The natural and medical history of the principality of the Asturias |title= Classic Descriptions of Disease |editor1-last= Major |editor1-first= R. H. |edition= 3rd  |location= Springfield |publisher= Charles C. Thomas  |pages= 607–12}}</ref> His work published in 1762 by his friend Juan Sevillano was titled {{lang|es|Historia Natural y Medicina del Principado de Asturias}} or ''Natural and Medical History of the Principality of Asturias'' (1762). This led to the disease being known as "Asturian [[leprosy]]", and it is recognized as the first modern pathological description of a syndrome.<ref>{{cite journal |last1= Stratigos |first1= J. D. |last2= Katsambas |first2= A. |date= 1977 |title= Pellagra: A still existing disease |journal= British Journal of Dermatology |volume= 96 |issue= 1 |pages= 99–106 |pmid= 843444 |s2cid= 10284450 |doi= 10.1111/j.1365-2133.1977.tb05197.x }}</ref> It was an endemic disease in [[northern Italy]], where it was named, from [[lombard language|Lombard]], by Francesco Frapolli of [[Milan]].<ref>{{cite web| title = Definition of Pellagra| work = MedicineNet.com| url = http://www.medterms.com/script/main/art.asp?articlekey=4821| access-date = 18 June 2007| url-status = live| archive-url = https://web.archive.org/web/20070930155704/http://www.medterms.com/script/main/art.asp?articlekey=4821| archive-date = 30 September 2007}}</ref> With pellagra affecting over 100,000 people in Italy by the 1880s, debates raged as to how to classify the disease (as a form of [[scurvy]], [[elephantiasis]] or as something new), and over its causation. In the 19th century, Roussel started a campaign in France to restrict consumption of maize and eradicated the disease in France, but it remained endemic in many rural areas of Europe.<ref>{{cite journal |last= Semba |first= R. D. |date= 2000 |title= Théophile Roussel and the elimination of pellagra from 19th century France |volume= 16 |issue= 3 |pages= 231–33 |journal= Nutrition |pmid= 10705082 |doi= 10.1016/S0899-9007(99)00273-7}}</ref> Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the most convincing hypothesis during the late 19th century, as espoused by [[Cesare Lombroso]], was that the maize either carried a toxic substance or was a carrier of disease.<ref>{{cite book |last= Cesare |first= Lombroso |date= 1869 |title= Studi clinici ed esperimentali sulla natura, causa e terapia delle pellagra |language= it |location= Bologna |publisher= Fava e Garagnani }}</ref> Louis Sambon, an Anglo-Italian doctor working at the [[London School of Hygiene & Tropical Medicine|London School of Tropical Medicine]], was convinced that pellagra was carried by an insect, along the lines of [[malaria]]. Later, the lack of pellagra outbreaks in [[Mesoamerica]], where maize is a major food crop, led researchers to investigate processing techniques in that region.

[[File:Joseph Goldberger 01.jpg|thumb|150px|right|[[Joseph Goldberger|Dr. Joseph Goldberger]]]]

Pellagra was studied mostly in Europe until the late 19th century when it became epidemic especially in the southern United States.<ref>{{cite journal |last1= Sydenstricker |first1=V. P. |date= 1958 |title= The history of pellagra, its recognition as a disorder of nutrition and its conquest |volume= 6 |issue= 4 |pages= 409–14 |journal= The American Journal of Clinical Nutrition |pmid= 13559167 |doi= 10.1093/ajcn/6.4.409 }}</ref><ref name=":2">{{Cite journal|last1=Clay|first1=Karen|last2=Schmick|first2=Ethan|last3=Troesken|first3=Werner|date=August 2017|title=The Rise and Fall of Pellagra in the American South|journal=NBER Working Paper No. 23730|doi=10.3386/w23730|s2cid=51988207|url=http://www.nber.org/papers/w23730.pdf|doi-access=free|access-date=23 September 2019|archive-date=17 May 2018|archive-url=https://web.archive.org/web/20180517235720/https://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx|url-status=live}}</ref> In the early 1900s, pellagra reached epidemic proportions in the American South.<ref name=":2" /> Between 1906 and 1940 more than 3 million Americans were affected by pellagra with more than 100,000 deaths, yet the epidemic resolved itself right after dietary niacin fortification.<ref name="Bollet1992">{{cite journal |last= Bollet |first= Alfred Jay |date= 1992 |title= Politics and Pellagra: The Epidemic of Pellagra in the U.S. in the Early Twentieth Century |journal= The Yale Journal of Biology and Medicine |volume= 65 |issue= 3 |pages= 211–21 |pmc= 2589605 |pmid= 1285449 |url= http://europepmc.org/articles/pmc2589605/pdf/yjbm00051-0058.pdf |access-date= 3 November 2014 |url-status= live |archive-url= https://web.archive.org/web/20210828210552/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2589605&blobtype=pdf |archive-date = 28 August 2021 }}</ref> Pellagra deaths in South Carolina numbered 1,306 during the first ten months of 1915; 100,000 Southerners were affected in 1916. At this time, the scientific community held that pellagra was probably caused by a [[Microorganism|germ]] or some unknown [[toxin]] in corn.<ref name="Bollet1992" /> The Spartanburg Pellagra Hospital in [[Spartanburg, South Carolina]], was the first facility in the United States dedicated to discovering the cause of pellagra. It was established in 1914 with a special Congressional appropriation to the [[United States Public Health Service|U.S. Public Health Service]] (PHS) and set up primarily for research. In 1915, [[Joseph Goldberger|Dr. Joseph Goldberger]], assigned to study pellagra by the [[Surgeon General of the United States]], showed it was linked to diet by observing the outbreaks of pellagra in orphanages and mental hospitals.  Goldberger noted that children between the ages of 6 and 12 (but not older or younger children at the orphanages) and patients at the mental hospitals (but not doctors or nurses) were the ones who seemed most susceptible to pellagra.<ref name=":0">{{Cite journal|jstor = 4572932|title = The Prevention of Pellagra: A Test of Diet among Institutional Inmates|journal = Public Health Reports|volume = 30|issue = 43|pages = 3117–3131|last1 = Goldberger|first1 = Joseph|last2 = Waring|first2 = C. H.|last3 = Willets|first3 = David G.|year = 1915|doi = 10.2307/4572932}}</ref> Goldberger theorized that a lack of meat, milk, eggs, and legumes made those particular populations susceptible to pellagra.  By modifying the diet served in these institutions with "a marked increase in the fresh animal and the leguminous protein foods," Goldberger was able to show that pellagra could be prevented.<ref name=":0" /> By 1926, Goldberger established that a diet that included these foods, or a small amount of [[brewer's yeast]],<ref name=Swan_2005>{{cite journal |doi=10.1353/bhm.2005.0046 |title=Goldberger's War: The Life and Work of a Public Health Crusader (review) |year=2005 |last1=Swan |first1=P. |s2cid=71873427 |journal=Bulletin of the History of Medicine |volume=79 |issue=1 |pages=146–47}}</ref> prevented pellagra.

Goldberger experimented on 11 prisoners (one was dismissed because of [[prostatitis]]). Before the experiment, the prisoners were eating the prison fare fed to all inmates at Rankin Prison Farm in Mississippi.<ref name=":1">{{Cite journal |last= Harkness |first= J. M. |date= 1996 |title= Prisoners and Pellagra |pmc= 1381793 |pmid= 8837636 |volume= 111 |issue= 5 |journal= Public Health Rep |pages= 463–67 }}</ref> Goldberger started feeding them a restricted diet of [[grits]], syrup, [[Mush (cornmeal)|mush]], biscuits, cabbage, sweet potatoes, rice, collards, and coffee with sugar (no milk). Healthy white male volunteers were selected as the typical skin lesions were easier to see in Caucasians and this population was felt to be those least susceptible to the disease, and thus provide the strongest evidence that the disease was caused by a nutritional deficiency. Subjects experienced mild, but typical cognitive and gastrointestinal symptoms, and within five months of this cereal-based diet, 6 of the 11 subjects broke out in the skin lesions that are necessary for a definitive diagnosis of pellagra. The lesions appeared first on the scrotum.<ref name="GoldbergerWheeler1915">{{Cite journal |last1= Goldberger |first1= Joseph |last2= Wheeler |first2= G. A. |date= 12 November 1915 |title= Experimental Pellagra in the Human Subject Brought about by a Restricted Diet |journal= Public Health Reports |volume= 30 |issue= 46 |pages= 3336–3339 |doi= 10.2307/4572984 |jstor= 4572984 }}</ref> Goldberger was not given the opportunity to experimentally reverse the effects of diet-induced pellagra as the prisoners were released shortly after the diagnoses of pellagra were confirmed.<ref name=":1" /> In the 1920s, he connected pellagra to the corn-based diets of rural areas rather than infection as contemporary medical opinion would suggest.<ref name="GoldbergerWheeler1915"/><ref>{{cite journal |last1= Goldberger |first1= J. |title= The etiology of pellagra. 1914 |journal= Public Health Reports |year= 2006 |volume= 121 |issue= Suppl 1 |pages= 77–79; discussion 76 |pmid= 16550768 }}</ref> Goldberger believed that the root cause of pellagra amongst Southern farmers was limited diet resulting from poverty, and that social and land reform would cure epidemic pellagra. His reform efforts were not realized, but [[Agricultural diversification|crop diversification]] in the Southern United States, and the accompanying improvement in diet, dramatically reduced the risk of pellagra.<ref>{{cite journal |last1= Wolf |first1= R. |last2= Orion |first2= E. |last3= Matz |first3= H. |last4= Tüzün |first4= Y. |last5= Tüzün |first5= B. |date= 2002 |title= Miscellaneous treatments, II: Niacin and heparin: Unapproved uses, dosages, or indications |volume= 20 |issue= 5 |pages= 547–57 |journal= Clinics in Dermatology |pmid= 12435525 |doi= 10.1016/S0738-081X(02)00268-7}}</ref> Goldberger is remembered as the "unsung hero of American clinical epidemiology".<ref>{{cite journal |pmid= 8042827 |year= 1994 |last1= Elmore |first1= J. G. |last2= Feinstein |first2= A. R. |s2cid= 13226008 |title= Joseph Goldberger: An unsung hero of American clinical epidemiology |volume= 121 |issue= 5 |pages= 372–75 |journal= Annals of Internal Medicine |doi= 10.7326/0003-4819-121-5-199409010-00010}}</ref> Though he identified that a missing nutritional element was responsible for pellagra, he did not discover the specific vitamin responsible.

In 1937, [[Conrad Elvehjem]], a biochemistry professor at the [[University of Wisconsin-Madison]], showed that the vitamin B<sub>3</sub> cured pellagra (manifested as [[Black hairy tongue|black tongue]]) in dogs. Later studies by Dr. [[Tom Spies]], Marion Blankenhorn, and Clark Cooper established that niacin also cured pellagra in humans, for which ''Time'' Magazine dubbed them its 1938 [[Time Person of the Year|Men of the Year]] in comprehensive science.<ref name="Sachs2003">{{Cite book|last=Sachs|first=Ruth|url=https://books.google.com/books?id=WOPfM-0hz1AC&q=%22pellagra%3A+Drs.+Tom+Douglas%22&pg=PA630|title=White Rose History, Volume I: Coming Together (January 31, 1933 – April 30, 1942)|date=November 2003|publisher=Exclamation! Publishers|isbn=978-0-9710541-9-6|language=en|at=Appendix D, p. 2|quote=Men of the Year, outstanding in comprehensive science were three medical researchers who discovered that nicotinic acid was a cure for human pellagra: Drs. Tom Douglas Spies of Cincinnati General Hospital, Marion Arthur Blankenhorn of the University of Cincinnati, Clark Niel Cooper of Waterloo, Iowa.|access-date=27 June 2023|archive-date=15 July 2023|archive-url=https://web.archive.org/web/20230715054846/https://books.google.com/books?id=WOPfM-0hz1AC&q=%22pellagra%3A+Drs.+Tom+Douglas%22&pg=PA630|url-status=live}}</ref>

Research conducted between 1900 and 1950 found the number of cases of women with pellagra was consistently double the number of cases of affected men.<ref name=pmid637029>{{cite journal |last= Miller |first= D. F. |date= 1978 |title= Pellagra deaths in the United States |journal= Am. J. Clin. Nutr. |volume= 31 |issue= 4 |pages= 558–59 |pmid= 637029 |doi= 10.1093/ajcn/31.4.558 }}</ref> This is thought to be due to the inhibitory effect of [[estrogen]] on the conversion of the amino acid tryptophan to nicotinic acid mononucleotide (NaMN).<ref>{{cite journal |doi=10.1525/nua.2000.23.1.20 |title=Pellagra, Sex and Gender: Biocultural Perspectives on Differential Diets and Health |year=2000 |last1=Brenton |first1=B. P. |journal=Nutritional Anthropology |volume=23 |issue=1 |pages=20–24}}</ref> Some researchers of the time gave a few explanations regarding the difference.<ref>{{cite book |last= Carpenter |first= K. |date= 1981 |title= Pellagra |publisher= Hutchinson Ross Pub. Co |location= Stroudsburg, Pennsylvania |isbn= 978-0-87933-364-5 }}{{page needed|date=January 2014}}</ref>

Gillman and Gillman related skeletal tissue and pellagra in their research in South Africans. They provide some of the best evidence for skeletal manifestations of pellagra and the reaction of bone in malnutrition. They claimed radiological studies of adult pellagrins demonstrated marked [[osteoporosis]]. A negative mineral balance in pellagrins was noted, which indicated active mobilization and excretion of endogenous mineral substances, and undoubtedly impacted the turnover of bone. Extensive dental caries were present in over half of pellagra patients. In most cases, [[caries]] were associated with "severe [[gingival retraction]], [[sepsis]], exposure of [[cementum]], and loosening of teeth".<ref>{{cite book |last1= Gillman |first1= J. |last2= Gillman |first2= T. |date= 1951 |title= Perspectives in Human Malnutrition: A Contribution to the Biology of Disease from a Clinical and Pathological Study of Chronic Malnutrition and Pellagra in the African |publisher= Grune and Stratton |location= New York }}{{page needed|date=January 2014}}</ref>

=== United States ===
{{nutritionalvalue | name=Corn grits, yellow<br /> unenriched, dry
| protein=8.8 g
| tryptophan=0.062 g
| niacin_mg=1.2
}}
{{nutritionalvalue | name=Peanut, valencia, raw
| protein=25 g
| tryptophan=0.2445 g
| niacin_mg=12.9
}}

Pellagra was first reported in 1902 in the United States, and has "caused more deaths than any other nutrition-related disease in American history", reaching epidemic proportions in the American South during the early 1900s.<ref name=":2" /> Poverty and consumption of corn were the most frequently observed risk factors, but the exact cause was not known, until groundbreaking work by [[Joseph Goldberger]].<ref name="Rajakumar2000"/> A 2017 National Bureau of Economic Research paper explored the role of cotton production in the emergence of disease; one prominent theory is that "widespread cotton production had displaced local production of niacin-rich foods and driven poor Southern farmers and mill workers to consume milled Midwestern corn, which was relatively cheap but also devoid of the niacin necessary to prevent pellagra."<ref name=":2" /> The study provided evidence in favor of the theory: there were lower pellagra rates in areas where farmers had been forced to abandon cotton production (a highly profitable crop) in favor of food crops (less profitable crops) due to [[boll weevil]] infestation of cotton crops (which occurred randomly).<ref name=":2" />

Pellagra developed especially among the vulnerable populations in institutions such as orphanages and prisons, because of the monotonous and restricted diet. Soon pellagra began to occur in epidemic proportions in states south of the [[Potomac River|Potomac]] and [[Ohio River|Ohio river]]s. The pellagra epidemic lasted for nearly four decades beginning in 1906.<ref name="Bollet1992" /> It was estimated that there were 3 million cases, and 100,000 deaths due to pellagra during the epidemic.<ref name="Rajakumar2000" />

The pellagra epidemic in the American south had subsided in periods of low cotton production (late 1910s to early 1920s, the Great Depression), but it had consistently rebounded as cotton production recovered. The cause would not be understood until 1937, when the relation with niacin was discovered.<ref name="Sachs2003"/> Voluntary [[food fortification]] and periods of mandatory fortification on the state and federal levels soon followed, coinciding with a continuous drop in pellagra deaths. By the 1950s, the disease was virtually eliminated from the US.<ref name=":2" />

==== Corn processing ====
The whole dried corn kernel contains a nutritious [[Cereal germ|germ]] and a thin [[Bran|seed coat]] that provides some fiber.<ref>{{cite web|last1=Fletcher|first1=Janet|title=Waves of Grain / Grain glossary|url=http://www.sfgate.com/food/article/WAVES-OF-GRAIN-Grain-glossary-2702987.php|website=San Francisco Chronicle|publisher=Hearst|access-date=2 October 2014|url-status=live|archive-url=https://web.archive.org/web/20141006084556/http://www.sfgate.com/food/article/WAVES-OF-GRAIN-Grain-glossary-2702987.php|archive-date=6 October 2014|date=26 January 2005}}</ref> There are two important considerations for using ground whole-grain corn.
# The germ contains oil that is exposed by grinding, thus whole-grain cornmeal and grits turn rancid quickly at room temperature and should be refrigerated.
# Whole-grain cornmeal and grits require extended cooking times as seen in the following cooking directions for whole-grain grits: {{blockquote|"Place the grits in a pan and cover them with water. Allow the grits to settle a full minute, tilt the pan, and skim off and discard the chaff and hulls with a fine [[tea strainer]]. Cook the grits for 50 minutes if the grits were soaked overnight or else 90 minutes if not."<ref>{{cite web|title=Simple Buttered Antebellum Coarse Grits|url=http://ansonmills.com/recipes/489|website=Anson Mills|url-status=live|archive-url=https://web.archive.org/web/20141004135034/http://www.ansonmills.com/recipes/489|archive-date=2014-10-04}}</ref>}}

The milling of corn removes the [[aleurone]] and germ layers, removing much of the (already low) amounts of bioavailable niacin and tryptophan found within.<ref name=fao92/>{{rp|at=&sect;5.3}}{{efn|Using corn as the sole source of food carries a risk of pellagra and other nutritional deficiencies, because directly ground, untreated corn contains neither sufficient niacin nor enough digestible tryptophan. The Mesoamerican civilizations developed [[nixtamalization]], which entails pre-processing corn by soaking in an alkaline solution. Doing so prevents pellagra by increasing the digestibility of tryptophan-containing proteins. They furthermore combined corn with legumes to form a complete protein.<ref name=fao92>{{cite book |title=Maize in human nutrition |date=1992 |publisher=Food and Agriculture Organization of the United Nations |location=Rome |isbn=9789251030134|url=https://www.fao.org/3/T0395E/T0395E00.htm}} &ndash; Section 5.2 "Lime-treated maize (part II)", Section 5.3 "Arepas", Section 8 "Improvement of maize diets"</ref>{{rp|&sect;5.2,&sect;8}} (Several sources repeat a claim that corn contains "{{not a typo|niacytin}}", niacin bound up in a complex with [[hemicellulose]] which is nutritionally unavailable. They claim that niacytin is up to 90% of the total niacin content in grain, and that [[nixtamalization]] prevents pellagra by librating this niacin.<ref>{{cite book |last1= Ball |first1= George F. M. |title= Vitamins in Foods: Analysis, Bioavailability, and Stability; Food Science and Technology |date= 2005 |publisher= CRC Press |isbn= 978-1-4200-2697-9 |page= 183 |url= https://books.google.com/books?id=mcwdkygB0FQC |url-status= live |archive-url= https://web.archive.org/web/20170415000103/https://books.google.com/books?id=mcwdkygB0FQC |archive-date= 15 April 2017}}</ref> However, a long line of evidence shows that nixtamalization has no effect on the niacin content of corn.<ref name=fao92/>{{rp|&sect;5.2}})}} The milling and degerming of corn in the preparation of cornmeal became feasible with the development of the [[Beall degerminator]], which was originally patented in 1901 and was used to separate the grit from the germ in corn processing.<ref>{{cite web|title=Beall Degerminators General Information|url=http://www.bealldeg.com/generalinfo.html|website=Beall Degerminators|publisher=Beall Degerminator Company|access-date=2 October 2014|url-status=usurped|archive-url=https://web.archive.org/web/20140426004841/http://www.bealldeg.com/generalinfo.html|archive-date=26 April 2014}}</ref> [[Casimir Funk]], who helped elucidate the role of [[thiamin]] in the [[etiology]] of [[beriberi]], was an early investigator of the problem of pellagra. Funk suggested that a change in the method of milling corn was responsible for the outbreak of pellagra,<ref>{{cite journal |last= Funk |first= C. |date= 1913 |title= Studies on pellagra. The influence of the milling of maize on the chemical composition and nutritive value of the meal |journal= J Physiol |volume= 47 |issue= 4–5 |pages= 389–92 |doi= 10.1113/jphysiol.1913.sp001631 |pmid= 16993244 |pmc= 1420484 }}</ref> but no attention was paid to his article on this subject.<ref name="Bollet1992" />

==In popular culture==
* [[George Sessions Perry]]'s 1941 novel ''Hold Autumn in Your Hand''{{snd}}and [[Jean Renoir]]'s 1945 film adaptation of it, ''[[The Southerner (film)|The Southerner]]''{{snd}}incorporates pellagra ("spring sickness") as a major plot element in the story of an impoverished Texas farm family.<ref>{{Cite web|date=May 1999|first=Don|last=Graham|title=Cotton Tale|url=https://www.texasmonthly.com/articles/cotton-tale/|access-date=11 February 2023|website=[[Texas Monthly]]|language=en|archive-date=20 December 2017|archive-url=https://web.archive.org/web/20171220140211/https://www.texasmonthly.com/articles/cotton-tale/|url-status=live}}</ref>
* Satirical singer/pianist [[Tom Lehrer]] referred to pellagra as an endemic disease of the Southern states in the lyrics of his 1960 song "I Wanna Go Back to Dixie" -- "I'll go back to the Swanee / Where pellagra makes ya scrawny / And the honeysuckle clutters up the vine."<ref>{{Cite web |last=Lehrer |first=Tom |date=26 June 2024 |title=I Wanna Go Back to Dixie |url=https://tomlehrersongs.com/wp-content/uploads/2018/12/i-wanna-go-back-to-dixie.pdf }}</ref>
* Season 2, Episode 22 of [[House (TV series)|House]], titled "[[Forever (House episode)|Forever]]", focuses on a new mother diagnosed with Pellagra who experiences aggression and homicidal tendencies 

== References ==
{{notelist}}
{{Reflist}}

== Further reading ==
* {{cite encyclopedia |last= Beardsley |first= E. |date= 2006 |title= The Spartanburg Pellagra Hospital |encyclopedia= The South Carolina Encyclopedia |publisher= University of South Carolina Press |location= Columbia, South Carolina |isbn= 1-57003-598-9}}
* {{cite journal |last= Crabb |first= Mary Katherine |date= 1992 |title= An Epidemic of Pride: Pellagra and the Culture of the American South |journal= Anthropologica |volume= 34 |issue= 1 |pages= 89–103 |doi= 10.2307/25605634 |jstor= 25605634 }}
* {{cite journal |last1= Hampl |first1= J. S. |last2= Hampl |first2= W. S. |date= 1 November 1997 |title= Pellagra and the origin of a myth: evidence from European literature and folklore |journal= [[Journal of the Royal Society of Medicine]] |volume= 90 |issue= 11 |pages= 636–39 |pmc= 1296679 |pmid= 9496281 |doi= 10.1177/014107689709001114}}
* {{cite journal |last= Hendrick |first= Burton J. |date= April 1916  |title= The Mastery of Pellagra: The Mysterious Disease, Almost Unknown in This Country Fifteen Years Ago, That Now Claims 7,500 Victims A Year And Is Spreading Rapidly |journal= [[World's Work|The World's Work: A History of Our Time]] |volume= XXXI |pages= 633–39 |url= https://books.google.com/books?id=09_Sr9emceQC&pg=PA633}}
* {{cite web |last= Kraut |first= Alan |date= 3 September 2010 |title= Dr. Joseph Goldberger and the War on Pellagra |website= Office of NIH History |publisher= [[National Institutes of Health]] |url= http://history.nih.gov/exhibits/goldberger/docs/pellegra_5.htm |url-status= dead |archive-url= https://web.archive.org/web/20041022004508/http://history.nih.gov/exhibits/goldberger/docs/pellegra_5.htm |archive-date= 2004-10-22}}
* {{cite journal |author= <!-- not stated --> |date= 1916 |title= Reports and Resolutions of the General Assembly of the State of South Carolina, Regular Session Commencing January 11, 1916 |journal= Annual Report of the State Board of Health (1915–1916) |location= Columbia, South Carolina |volume= 4 |publisher= Gonzales and Bryan, state printers }}
* {{cite journal |last1= Swain |first1= C. P. |last2= Tavill |first2= A. S. |last3= Neale |first3= G. |date= September 1976 |title= Studies of tryptophan and albumin metabolism in a patient with carcinoid syndrome, pellagra, and hypoproteinemia |journal= Gastroenterology |volume= 71 |issue= 3 |pages= 484–89 |pmid= 133045 |doi= 10.1016/s0016-5085(76)80460-x |doi-access= free }}

== External links ==
* {{cite EB1911|wstitle= Pellagra | volume= 21 | page = 69 |short= 1}}
* [http://www.fao.org/DOCREP/W0073e/w0073e05.htm#P4008_468640 Pellagra]{{snd}}[[Food and Agriculture Organization]] (FAO)
{{Medical resources
| meshName        = Pellagra
| meshNumber      = C18.654.521.500.133.699.529
| ICD10           = {{ICD10|E|52||e|50}}
| ICD9            = {{ICD9|265.2}}
| ICDO            =
| OMIM            =
| DiseasesDB      = 9730
| MedlinePlus     = 000342
| eMedicineSubj   = ped
| eMedicineTopic  = 1755
| SNOMED CT       = 418186002
| Orphanet        = 97352
}}

{{Nutritional pathology}}
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[[Category:Vitamin deficiencies]]
[[Category:Wikipedia medicine articles ready to translate]]
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