Pellagra

Pellagra is a

There are two main types of pellagra, primary and secondary.[1] Primary pellagra is due to a diet that does not contain enough niacin and tryptophan.^[1] Secondary pellagra is due to a poor ability to use the niacin within the diet.^[1] This can occur as a result of alcoholism, long-term diarrhea, carcinoid syndrome, Hartnup disease, and a number of medications such as isoniazid.^[1] Diagnosis is typically based on symptoms and may be assisted by urine testing.^[3]

Treatment is with either niacin or

The classic symptoms of pellagra are diarrhea, dermatitis, dementia, and death ("the four Ds").^[4] A more comprehensive list of symptoms includes:

• 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
• peripheral neuritis
  (nerve damage)
• Diarrhea
• Dilated cardiomyopathy (enlarged, weakened heart)
• Sensitivity to radiation
• Eventually dementia

J. Frostigs and

• 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[5]^[6]

Independently of clinical symptoms, blood level of tryptophan or urinary metabolites such as 2-pyridone/N-methylniacinamide ratio <2 or

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

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.^[10] Gastroenterostomy can also cause pellagra.^[10] Chronic alcoholism can also cause poor absorption, which combined with a diet already low in niacin and tryptophan produces pellagra.^[10] 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

If untreated, pellagra can kill within four or five years.[3] 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.^[12]

Epidemiology

Pellagra can be common in people who obtain most of their

The word pellagra is known to come from Lombard, but its exact origins are disputed. "Pell" certainly arises from classical Latin pellis, meaning "skin".^[22][23] "-agra" may arise from Lombard agra, meaning "like serum or holly juice",^[22] or the Latinate -agra,^[23] a suffix for maladies itself borrowed from the Greek ἄγρα, meaning "a catch-point, a hunting trap".^[24]

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.^[25] 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

Pellagra was studied mostly in Europe until the late 19th century when it became epidemic especially in the southern United States.

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.^[36] 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.^[37] 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.^[36] In the 1920s, he connected pellagra to the corn-based diets of rural areas rather than infection as contemporary medical opinion would suggest.^[38][39] 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.^[40] Goldberger is remembered as the "unsung hero of American clinical epidemiology".^[41] Though he identified that a missing nutritional element was responsible for pellagra, he did not discover the specific vitamin responsible.

In 1937,

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.[43] This is thought to be due to the inhibitory effect of estrogen on the conversion of the amino acid tryptophan to niacin.^[44] Some researchers of the time gave a few explanations regarding the difference.^[45]

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

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.[32] 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.^[49] 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."^[32] 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).^[32]

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 rivers. The pellagra epidemic lasted for nearly four decades beginning in 1906.^[50] It was estimated that there were 3 million cases, and 100,000 deaths due to pellagra during the epidemic.^[49]

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 niacin was discovered. 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 is virtually eliminated from the US.^[32]

Corn processing

The whole dried corn kernel contains a nutritious germ and a thin seed coat that provides some fiber.^[51] There are two important considerations for using ground whole-grain corn.

1. 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.
2. Whole-grain cornmeal and grits require extended cooking times as seen in the following cooking directions for whole-grain grits:

   "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."^[52]

The milling of corn removes the

• George Sessions Perry's 1941 novel Hold Autumn in Your Hand – and Jean Renoir'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.^[57]

References