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Pellagra is a
disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
caused by a lack of the vitamin
niacin Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Nicotinic acid is also a prescription medication. Amounts f ...
(vitamin B3). Symptoms include inflamed skin,
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
,
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, and sores in the mouth. Areas of the skin exposed to friction and radiation are typically affected first. Over time affected skin may become darker, stiffen, peel, or bleed. There are two main types of pellagra, primary and secondary. Primary pellagra is due to a diet that does not contain enough niacin and
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
. Secondary pellagra is due to a poor ability to use the niacin within the diet. This can occur as a result of
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
, long-term diarrhea,
carcinoid syndrome Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to neuroendocrine tumors (formerly known as carcinoid tumors). The syndrome is caused by neuroendocrine tumors most often found in the gut ...
,
Hartnup disease Hartnup disease (also known as " pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into se ...
, and a number of medications such as
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. F ...
. Diagnosis is typically based on symptoms and may be assisted by urine testing. Treatment is with either
nicotinic acid Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Nicotinic acid is also a prescription medication. Amounts f ...
or
nicotinamide Nicotinamide (International nonproprietary name, INN, British Approved Name, BAN ) or niacinamide (United States Adopted Name, USAN ) is a form of vitamin B3, vitamin B3 found in food and used as a dietary supplement and medication. As a suppl ...
supplementation. Improvements typically begin within a couple of days. General improvements in diet are also frequently recommended. Decreasing sun exposure via
sunscreen Sunscreen, also known as sunblock, sun lotion or sun cream, is a photoprotection, photoprotective topical product for the Human skin, skin that helps protect against sunburn and prevent skin cancer. Sunscreens come as lotions, sprays, gels, fo ...
and proper clothing is important while the skin heals. Without treatment death may occur. The disease occurs most commonly in the
developing world A developing country is a sovereign state with a less-developed industrial base and a lower Human Development Index (HDI) relative to developed countries. However, this definition is not universally agreed upon. There is also no clear agreeme ...
, often as a
disease of poverty Diseases of poverty, also known as poverty-related diseases (PRDs), are diseases that are more prevalent in low-income populations. They include infectious diseases, as well as diseases related to malnutrition and poor health behaviour. Poverty i ...
associated with
malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is a deficiency, excess, or imbalance of energy, protein and other nutrients which adversely affects the body's tissues a ...
, specifically
sub-Saharan Africa Sub-Saharan Africa is the area and regions of the continent of Africa that lie south of the Sahara. These include Central Africa, East Africa, Southern Africa, and West Africa. Geopolitically, in addition to the list of sovereign states and ...
.


Etymology

The word ' is known to come from Lombard, but its exact origins are disputed. "Pell" certainly arises from classical Latin , meaning "skin". "-agra" may arise from Lombard , meaning "like
serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...
or
holly ''Ilex'' () or holly is a genus of over 570 species of flowering plants in the family Aquifoliaceae, and the only living genus in that family. ''Ilex'' has the most species of any woody dioecious angiosperm genus. The species are evergreen o ...
juice", or the Latinate , a suffix for maladies itself borrowed from the Greek , meaning "a catch-point, a hunting trap".


Signs and symptoms

The classic symptoms of pellagra are
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
,
dermatitis Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
,
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, and death ("the four Ds"). A more comprehensive list of symptoms includes: *
Dermatitis Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
(characteristic "broad collar" rash known as casal collar) *
Hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
* Swelling * Smooth, beefy red
glossitis Glossitis can mean soreness of the tongue, or more usually inflammation with depapillation of the dorsal surface of the tongue (loss of the lingual papillae), leaving a smooth and erythematous (reddened) surface, (sometimes specifically termed atro ...
(tongue inflammation) *
Trouble sleeping Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
*
Weakness Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...
*
Mental confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
or
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
*
Ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
(lack of coordination), paralysis of extremities,
peripheral neuritis Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
(nerve damage) *
Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
*
Dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...
(enlarged, weakened heart) * Sensitivity to radiation * Eventually
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
J. Frostigs and Tom Spies—according to Cleary and Cleary—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 Independently of clinical symptoms, blood level of tryptophan or urinary metabolites such as
2-pyridone 2-Pyridone is an organic compound with the formula . It is a colourless solid. It is well known to form hydrogen bonded dimers and it is also a classic case of a compound that exists as tautomers. Tautomerism The second tautomer is 2-hydroxy ...
/ N-methylnicotinamide ratio <2 or
NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum, a series of geographic coordinate systems * North Atlantic Drift, an Atlantic Ocean current * Hobli, a subdivision of a taluka in southern Ind ...
/
NADP Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
ratio in
red blood cells Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
can diagnose pellagra. The diagnosis is confirmed by rapid improvements in symptoms after doses of nicotinamide (250–500 mg/day) or nicotinamide enriched food.


Pathophysiology

Pellagra can develop according to several mechanisms, classically as a result of niacin (vitamin B3) deficiency, which results in decreased
nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...
(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 Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
, an
essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life forms ...
found in meat, poultry, fish, eggs, and
peanut The peanut (''Arachis hypogaea''), also known as the groundnut, goober (US), goober pea, pindar (US) or monkey nut (UK), is a legume crop grown mainly for its edible seeds. It is widely grown in the tropics and subtropics by small and large ...
s, which the body uses to make niacin. Third, it may be caused by excess
leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...
, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of nicotinic acid to nicotinamide mononucleotide (NMN) causing pellagra-like symptoms to occur. Some conditions can prevent the absorption of dietary niacin or tryptophan and lead to pellagra. Inflammation of the
jejunum The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialized for the absorption by enterocytes of small nutrient molecules which have been pr ...
or
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...
can prevent nutrient absorption, leading to pellagra, and this can in turn be caused by
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
.
Gastroenterostomy A gastroenterostomy is the surgical creation of a connection between the stomach and the jejunum. The operation can sometimes be performed at the same time as a partial gastrectomy (the removal of part of the stomach). Gastroenterostomy was in th ...
can also cause pellagra. Chronic
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
can also cause poor absorption, which combined with a diet already low in niacin and tryptophan produces pellagra.
Hartnup disease Hartnup disease (also known as " pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into se ...
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 Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to neuroendocrine tumors (formerly known as carcinoid tumors). The syndrome is caused by neuroendocrine tumors most often found in the gut ...
, a disease in which neuroendocrine tumors along the GI tract use tryptophan as the source for
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
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 B6 and reduce niacin synthesis, since B6 (pyridoxine) is a required cofactor in the tryptophan-to-niacin reaction. Several therapeutic drugs can provoke pellagra. These include the antibiotics
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. F ...
, which decreases available B6 by binding to it and making it inactive, so it cannot be used in niacin synthesis, and
chloramphenicol Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by intravenous, injection into a vein, it is used to treat meningitis, pl ...
; the anti-cancer agent
fluorouracil Fluorouracil (5-FU, 5-fluorouracil), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stoma ...
; and the
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...
mercaptopurine Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's d ...
.


Treatment

If untreated, pellagra can kill within four or five years. Treatment is with
nicotinamide Nicotinamide (International nonproprietary name, INN, British Approved Name, BAN ) or niacinamide (United States Adopted Name, USAN ) is a form of vitamin B3, vitamin B3 found in food and used as a dietary supplement and medication. As a suppl ...
, 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.


Epidemiology

Pellagra can be common in people who obtain most of their
food energy Food energy is chemical energy that animals and humans derive from food to sustain their metabolism and muscular activity. Most animals derive most of their energy from aerobic respiration, namely combining the carbohydrates, fats, and protein ...
from
corn Maize (; ''Zea mays''), also known as corn in North American English, is a tall stout Poaceae, grass that produces cereal grain. It was domesticated by indigenous peoples of Mexico, indigenous peoples in southern Mexico about 9,000 years ago ...
, notably rural
South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a considerably smaller portion in the Northern Hemisphere. It can also be described as the southern Subregion#Americas, subregion o ...
, where maize is a
staple food A staple food, food staple, or simply staple, is a food that is eaten often and in such quantities that it constitutes a dominant portion of a standard diet for an individual or a population group, supplying a large fraction of energy needs an ...
. If maize is not nixtamalized, it is a poor source of tryptophan, as well as niacin. Nixtamalization corrects the niacin deficiency, and is a common practice in
Native American Native Americans or Native American usually refers to Native Americans in the United States. Related terms and peoples include: Ethnic groups * Indigenous peoples of the Americas, the pre-Columbian peoples of North, South, and Central America ...
cultures that grow corn, but most especially in
Mexico Mexico, officially the United Mexican States, is a country in North America. It is the northernmost country in Latin America, and borders the United States to the north, and Guatemala and Belize to the southeast; while having maritime boundar ...
and the countries of
Central America Central America is a subregion of North America. Its political boundaries are defined as bordering Mexico to the north, Colombia to the southeast, the Caribbean to the east, and the Pacific Ocean to the southwest. Central America is usually ...
. 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 Endemism is the state of a species being found only in a single defined geographic location, such as an island, state, nation, country or other defined zone; organisms that are indigenous to a place are not endemic to it if they are also foun ...
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 Joseph Goldberger (, ) (July 16, 1874 – January 17, 1929) was an American physician and epidemiologist in the United States Public Health Service (PHS). As a public health official, he was an advocate for scientific and social recognition of th ...
. 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. Pellagra was common among prisoners of Soviet labor camps (the
Gulag The Gulag was a system of Labor camp, forced labor camps in the Soviet Union. The word ''Gulag'' originally referred only to the division of the Chronology of Soviet secret police agencies, Soviet secret police that was in charge of runnin ...
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 Humanitarian aid is material and logistic assistance, usually in the short-term, to people in need. Among the people in need are the homeless, refugees, and victims of natural disasters, wars, and famines. The primary objective of humanitarian ...
. Refugees typically rely on limited sources of vitamin B3 provided to them, often
peanut The peanut (''Arachis hypogaea''), also known as the groundnut, goober (US), goober pea, pindar (US) or monkey nut (UK), is a legume crop grown mainly for its edible seeds. It is widely grown in the tropics and subtropics by small and large ...
s (which, in Africa, may be supplied in place of local groundnut staples, such as the 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. 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. 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 (
psychotropic A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...
,
cytostatic Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division and induce cell death. Cytostasis is an important prerequisite ...
, tuberculostatic or
analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
s),
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
, vitamin B2 and B6 deficiency, or malabsorption syndromes such as
Hartnup disease Hartnup disease (also known as " pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into se ...
and
carcinoid tumors A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) a ...
.


History

Native American Native Americans or Native American usually refers to Native Americans in the United States. Related terms and peoples include: Ethnic groups * Indigenous peoples of the Americas, the pre-Columbian peoples of North, South, and Central America ...
cultivators who first domesticated corn (
maize Maize (; ''Zea mays''), also known as corn in North American English, is a tall stout grass that produces cereal grain. It was domesticated by indigenous peoples in southern Mexico about 9,000 years ago from wild teosinte. Native American ...
) prepared it by
nixtamalization Nixtamalization ( ) is a process for the preparation of maize (corn), or other cereal grain, grain, in which the grain is soaked and cooking, cooked in an alkaline solution, usually limewater (but sometimes aqueous alkali metal carbonates), ...
, in which the grain is treated with a solution of
alkali In chemistry, an alkali (; from the Arabic word , ) is a basic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of a soluble base has a pH greater than 7.0. The a ...
such as
lime Lime most commonly refers to: * Lime (fruit), a green citrus fruit * Lime (material), inorganic materials containing calcium, usually calcium oxide or calcium hydroxide * Lime (color), a color between yellow and green Lime may also refer to: Bo ...
. Nixtamalization makes the niacin nutritionally available and prevents pellagra. 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 Gaspar Roque Francisco Narciso Casal Julian (31 December 1681 – 10 August 1759) was a Spanish physician remembered for describing the Casal collar in pellagra. Casal was born in Girona Catalonia, Spain to Federico Casal y Dajón and Magdalena ...
. 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. His work published in 1762 by his friend Juan Sevillano was titled ''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 Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...
", and it is recognized as the first modern pathological description of a syndrome. It was an endemic disease in
northern Italy Northern Italy (, , ) is a geographical and cultural region in the northern part of Italy. The Italian National Institute of Statistics defines the region as encompassing the four Northwest Italy, northwestern Regions of Italy, regions of Piedmo ...
, where it was named, from Lombard, by Francesco Frapolli of
Milan Milan ( , , ; ) is a city in northern Italy, regional capital of Lombardy, the largest city in Italy by urban area and the List of cities in Italy, second-most-populous city proper in Italy after Rome. The city proper has a population of nea ...
. 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 Scurvy is a deficiency disease (state of malnutrition) resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, fatigue, and sore arms and legs. Without treatment, anemia, decreased red blood cells, gum d ...
,
elephantiasis Elephantiasis, often incorrectly called elephantitis, is the enlargement and hardening of limbs or body parts due to tissue swelling (edema). It is characterised by edema, hypertrophy, and fibrosis of skin and subcutaneous tissues, due to obstru ...
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. 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 Cesare Lombroso ( , ; ; born Ezechia Marco Lombroso; 6 November 1835 – 19 October 1909) was an Italian eugenicist, criminologist, phrenologist, physician, and founder of the Italian school of criminology. He is considered the founder of m ...
, was that the maize either carried a toxic substance or was a carrier of disease. Louis Sambon, an Anglo-Italian doctor working at the
London School of Tropical Medicine London is the capital and largest city of both England and the United Kingdom, with a population of in . Its wider metropolitan area is the largest in Western Europe, with a population of 14.9 million. London stands on the River Tha ...
, was convinced that pellagra was carried by an insect, along the lines of
malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
. Later, the lack of pellagra outbreaks in
Mesoamerica Mesoamerica is a historical region and cultural area that begins in the southern part of North America and extends to the Pacific coast of Central America, thus comprising the lands of central and southern Mexico, all of Belize, Guatemala, El S ...
, where maize is a major food crop, led researchers to investigate processing techniques in that region. Pellagra was studied mostly in Europe until the late 19th century when it became epidemic especially in the southern United States. In the early 1900s, pellagra reached epidemic proportions in the American South. 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. 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
germ Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during embry ...
or some unknown
toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
in corn. The Spartanburg Pellagra Hospital in
Spartanburg, South Carolina Spartanburg is a city in and the county seat of Spartanburg County, South Carolina, United States. The city had a population of 38,732 as of the 2020 United States census, 2020 census, making it the List of municipalities in South Carolina, 11th ...
, 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
U.S. Public Health Service The United States Public Health Service (USPHS or PHS) is a collection of agencies of the Department of Health and Human Services which manages public health, containing nine out of the department's twelve operating divisions. The assistant se ...
(PHS) and set up primarily for research. In 1915, Dr. Joseph Goldberger, assigned to study pellagra by the
Surgeon General of the United States The surgeon general of the United States is the operational head of the United States Public Health Service Commissioned Corps (PHSCC) and thus the leading spokesperson on matters of public health in the federal government of the United States. T ...
, 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. 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. By 1926, Goldberger established that a diet that included these foods, or a small amount of
brewer's yeast ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
, prevented pellagra. Goldberger experimented on 11 prisoners (one was dismissed because of
prostatitis Prostatitis is an umbrella term for a variety of medical conditions that incorporate bacterial and non-bacterial origin illnesses in the pelvic region. In contrast with the plain meaning of the word (which means "inflammation of the prostate"), the ...
). Before the experiment, the prisoners were eating the prison fare fed to all inmates at Rankin Prison Farm in Mississippi. Goldberger started feeding them a restricted diet of
grits Grits (stylized as GRITS) is an American Christian hip hop group from Nashville, Tennessee. Their name is an acronym, which stands for "Grammatical Revolution In the Spirit". GRITS is made up of Stacey "Coffee" Jones and Teron "Bonafide" Carter ...
, syrup,
mush In multiplayer online games, a MUSH (a backronymed variation on Multi-user dungeon, MUD most often expanded as Multi-User Shared Hallucination, though Multi-User Shared Hack, Habitat, and Holodeck are also observed) is a text-based online social m ...
, 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. 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. In the 1920s, he connected pellagra to the corn-based diets of rural areas rather than infection as contemporary medical opinion would suggest. 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 crop diversification in the Southern United States, and the accompanying improvement in diet, dramatically reduced the risk of pellagra. Goldberger is remembered as the "unsung hero of American clinical epidemiology". Though he identified that a missing nutritional element was responsible for pellagra, he did not discover the specific vitamin responsible. In 1937,
Conrad Elvehjem Conrad Arnold Elvehjem (May 27, 1901July 27, 1962) was internationally known as an American biochemist in nutrition. In 1937 he identified two vitamins, nicotinic acid, also known as niacin, and nicotinamide, which were deficient directly in hu ...
, a biochemistry professor at the
University of Wisconsin-Madison A university () is an institution of tertiary education and research which awards academic degrees in several academic disciplines. ''University'' is derived from the Latin phrase , which roughly means "community of teachers and scholars". Uni ...
, showed that the vitamin B3 cured pellagra (manifested as 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 Men of the Year in comprehensive science. 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. This is thought to be due to the inhibitory effect of
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
on the conversion of the amino acid tryptophan to nicotinic acid mononucleotide (NaMN). Some researchers of the time gave a few explanations regarding the difference. 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 Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. 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 Tooth decay, also known as caries,The word 'caries' is a mass noun, and is not a plural of 'carie'.'' is the breakdown of teeth due to acids produced by bacteria. The resulting cavities may be a number of different colors, from yellow to black ...
were associated with "severe gingival retraction,
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, exposure of
cementum Cementum is a specialized calcified substance covering the root of a tooth. The cementum is the part of the periodontium that attaches the teeth to the alveolar bone by anchoring the periodontal ligament. Structure The cells of cementum are ...
, and loosening of teeth".


United States

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. 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 Joseph Goldberger (, ) (July 16, 1874 – January 17, 1929) was an American physician and epidemiologist in the United States Public Health Service (PHS). As a public health official, he was an advocate for scientific and social recognition of th ...
. 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." 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 The boll weevil (''Anthonomus grandis'') is a species of beetle in the family Curculionidae. The boll weevil feeds on cotton buds and flowers. Thought to be native to Central Mexico, it migrated into the United States from Mexico in the late 19 ...
infestation of cotton crops (which occurred randomly). 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 and
Ohio river The Ohio River () is a river in the United States. It is located at the boundary of the Midwestern and Southern United States, flowing in a southwesterly direction from Pittsburgh, Pennsylvania, to its river mouth, mouth on the Mississippi Riv ...
s. The pellagra epidemic lasted for nearly four decades beginning in 1906. It was estimated that there were 3 million cases, and 100,000 deaths due to pellagra during the epidemic. 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. Voluntary
food fortification Food fortification is the addition of micronutrients (essential trace elements and vitamins) to food products. Food enrichment specifically means adding back nutrients lost during food processing, while fortification includes adding nutrients not ...
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.


Corn processing

The whole dried corn kernel contains a nutritious
germ Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during embry ...
and a thin
seed coat In botany, a seed is a plant structure containing an embryo and stored nutrients in a protective coat called a ''testa''. More generally, the term "seed" means anything that can be sown, which may include seed and husk or tuber. Seeds are the ...
that provides some fiber. 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: The milling of corn removes the
aleurone Aleurone (from Greek ''aleuron'', flour) is a protein found in protein granules of maturing seeds and tubers. The term also describes one of the two major cell types of the endosperm, the aleurone layer. The aleurone layer is the outermost layer of ...
and germ layers, removing much of the (already low) amounts of bioavailable niacin and tryptophan found within. 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.
Casimir Funk Casimir Funk ( ; February 23, 1884 – November 19, 1967) was a Polish biochemist generally credited with being among the first to formulate the concept of vitamins after publishing a landmark medical writing in 1912. He highlighted these "vita ...
, who helped elucidate the role of
thiamin Thiamine, also known as thiamin and vitamin B1, is a vitamin – an essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thiam ...
in the
etiology Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...
of
beriberi Thiamine deficiency is a medical condition of low levels of thiamine (vitamin B1). A severe and chronic form is known as beriberi. The name beriberi was possibly borrowed in the 18th century from the Sinhalese phrase (bæri bæri, “I canno ...
, 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, but no attention was paid to his article on this subject.


In popular culture

* George Sessions Perry's 1941 novel ''Hold Autumn in Your Hand''and
Jean Renoir Jean Renoir (; 15 September 1894 – 12 February 1979) was a French film director, screenwriter, actor, producer and author. His '' La Grande Illusion'' (1937) and '' The Rules of the Game'' (1939) are often cited by critics as among the greate ...
's 1945 film adaptation of it, '' The Southerner''incorporates pellagra ("spring sickness") as a major plot element in the story of an impoverished Texas farm family. * Satirical singer/pianist
Tom Lehrer Thomas Andrew Lehrer (; born April 9, 1928) is an American musician, singer-songwriter, satirist, and mathematician, who later taught mathematics and musical theater. He recorded pithy and humorous, often Music and politics, political songs that ...
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." * Season 2, Episode 22 of
House A house is a single-unit residential building. It may range in complexity from a rudimentary hut to a complex structure of wood, masonry, concrete or other material, outfitted with plumbing, electrical, and heating, ventilation, and air c ...
, titled "
Forever Forever or 4ever may refer to: Film and television Films * ''Forever'' (1921 film), an American silent film by George Fitzmaurice * ''Forever'' (1978 film), an American made-for-television romantic drama, based on the novel by Judy Blume * '' ...
", focuses on a new mother diagnosed with Pellagra who experiences aggression and homicidal tendencies


References


Further reading

* * * * * * Kraut, Alan.
Dr. Joseph Goldberger and the War on Pellagra, By Alan Kraut, Ph.D.
Office of History, National Institutes of Health. 3 September 2010. *


External links

*

ood and Agriculture Organization The Ood are an alien species with telepathic abilities from the long-running science fiction series ''Doctor Who''. In the series' narrative, they live in the distant future (circa 42nd century). The Ood are portrayed as a slave race, natural ...
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