pellagra pellagra pellagra is a disease caused by a lack of the vitamin niacin (vitamin b3). symptoms include inflamed skin, diarrhea, dementia, and sores in the mouth. areas of the skin exposed to either sunlight or friction are typically affected first. over time affected skin may become darker, stiffen, peel, or bleed. pellagrathe skin features of pellagra including peeling, redness, scaling, and thickening of sun-exposed areas.specialtydermatologysymptomsinflammation of the skin, diarrhea, dementia, sores in the mouthtypesprimary, secondarycausesnot enough niacindiagnostic methodbased on symptomsdifferential diagnosiskwashiorkor, pemphigus, photodermatitis, porphyriapreventionconsuming niacintreatmentniacin or nicotinamide supplementation.prognosisgood (with treatment), death in ~ 5 years (without treatment)frequencyrare (developed world), relatively common (developing world) 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. secondary pellagra is due to a poor ability to use the niacin within the diet. this can occur as a result of alcoholism, long-term diarrhea, carcinoid syndrome, hartnup disease, and a number of medications such as isoniazid. diagnosis is typically based on symptoms and may be assisted by urine testing. treatment is with either niacin or nicotinamide supplementation. improvements typically begin within a couple of days. general improvements in diet are also frequently recommended. decreasing sun exposure via sunscreen and proper clothing is important while the skin heals. without treatment death may occur. the disease occurs most commonly in the developing world, often as a disease of poverty associated with malnutrition, specifically sub-saharan africa. signs and symptoms this child has the casal collar skin rash around the neck associated with pellagra. man with pellagra with typical skin lesions the classic symptoms of pellagra are diarrhea, dermatitis, dementia, and death ("the four ds"). a more comprehensive list of symptoms includes: sensitivity to sunlight dermatitis (characteristic "broad collar" rash known as casal collar) hair loss swelling smooth, beefy red glossitis (tongue inflammation) trouble sleeping weakness mental confusion or aggression ataxia (lack of coordination), paralysis of extremities, peripheral neuritis (nerve damage) diarrhea dilated cardiomyopathy (enlarged, weakened heart) eventually dementia 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/n-methylniacinamide ratio <2 or nad/nadp ratio in red blood cells can diagnose pellagra. the diagnosis is confirmed by rapid improvements in symptoms after doses of niacin (250–500 mg/day) or niacin 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 (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, an essential amino acid found in meat, poultry, fish, eggs, and peanuts that the body uses to make niacin. third, it may be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (qprt) and inhibits the formation of niacin or 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 or ileum can prevent nutrient absorption, leading to pellagra, and this can in turn be caused by crohn's disease. gastroenterostomy can also cause pellagra. chronic alcoholism can also cause poor absorption which combines with a diet already low in niacin and tryptophan to produce pellagra. 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 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, which decreases available b6 by binding to it and making it inactive, so it cannot be used in niacin synthesis, and chloramphenicol; the anti-cancer agent fluorouracil; and the immunosuppressant mercaptopurine. treatment if untreated, pellagra can kill within four or five years. treatment is with nicotinamide, which has the same vitamin function as niacin 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 a girl in the london asylum in 1925 pellagra can be common in people who obtain most of their food energy from corn, notably rural south america, where maize is a staple food. 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 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 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. 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 gulags). 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 niacin provided to them, often peanuts (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, cytostatic, tuberculostatic or analgesics), hiv, vitamin b2 and b6 deficiency, or malabsorption syndromes such as hartnup disease and carcinoid tumors. etymology the word pellagra comes from the lombard words "pell" (skin) and "agra" (fem. sour). history 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 lime. 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. 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", and it is recognized as the first modern pathological description of a syndrome. it was an endemic disease in northern italy, where it was named, from lombard, as "pell agra" (agra = holly-like or serum-like; pell = skin) by francesco frapolli of milan. 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. 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. louis sambon, an anglo-italian doctor working at the 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. dr. joseph goldberger 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 or some unknown toxin in corn. the spartanburg pellagra hospital in spartanburg, south carolina, was the nation's first facility dedicated to discovering the cause of pellagra. it was established in 1914 with a special congressional appropriation to the u.s. public health service (phs) and set up primarily for research. in 1915, 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. 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, 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. goldberger started feeding them a restricted diet of grits, syrup, 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. 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