103 Pellagra

Pellagra is a recurring nutritional disease associ­ated with a severe deficiency of niacin, a vitamin of the B-complex group that includes both nicotinic acid and nicotinamide. Because the body can convert the essential amino acid tryptophan into niacin, in­clusion of enough tryptophan in the diet is as effec­tive as niacin in preventing the disease.

Pellagra is characterized by dermatitis, diarrhea, and dementia, and thus is known as the disease of the “3 D’s.” If untreated, a fourth “D,” death, may ensue. Before the cause of the disease was known, mortality was as high as 70 percent. As knowledge about the disease increased, however, and many mild cases, previously undiagnosed, were recog­nized, the mortality rate was reduced substantially.

Dermatitis is the characteristic symptom of pella­gra and the one on which diagnosis is based. Sym­metrical lesions appear on the hands and arms, on the tops of the feet and around the ankles, on the back of the neck, and across the face in a butterfly­shaped design. Weakness, a sense of malaise, and a reddened skin, sometimes confused with sunburn, are the first indications of the disease. Later the skin crusts and peels, revealing a smooth glossy skin underneath. In Spain, where the disease was first described in the eighteenth century, it was called mal de la rosa; in France, peasants named it mal de la mis&re. In Italy, it was called mal del sole because its peak came with the spring equinox. Late in the eighteenth century, the Italian physician Francesco Frapolli named the disease pellagra, which means “rough or dry skin.”

Distribution and Incidence

In the two centuries between 1730 and 1930, pella­gra caused much death and chronic misery, first in Europe, then in the Middle East, parts of Africa and Asia, and in North America.

The greatly reduced incidence of the disease in the United States may be attributed to a changed eco­nomic status in the South, where it was once preva­lent; to the widespread distribution of brewer’s yeast, which is a pellagra preventive; and to the enrichment of bread, flour, and cornmeal with vita­mins. An occasional diagnosis of pellagra is still made in the United States, usually in association with alcoholism or a malabsorption malady.

Even in those countries where pellagra continues to be a public health problem, it no longer appears in epidemic form, but rather in endemic foci. It is most likely to occur among agricultural workers whose diets are unsatisfactory, in adults rather than chil­dren, and in men rather than women.

Epidemiology and Etiology

Observations about pellagra made in Spain in the early eighteenth century have stood the test of time: The disease is associated with a maize diet and oc­curs mainly among the poor. These observations were repeated over the years, and their scientific validity was confirmed more than 200 years later by work done in the United States during the second and third decades of the twentieth century.

The U.S. Public Health Service, working in the southern states, linked pellagra conclusively to the peculiar “3 M” diet of the region - meat, meal, and molasses - and to the poverty of which this diet was a symbol. Bread made from cornmeal was the larg­est component of the pellagrin’s daily fare. Meat was pork fat back, and molasses was syrup made from cane. Widespread pellagra was found among tenant farmers and mill workers, in orphanages and mental institutions.

The missing element in the pellagrin’s diet at first was called the pellagra-preventing or “P-P” factor. Although its exact nature was unknown, it was proved to exist in a number of foods including meat, milk, eggs, and certain vegetables, particularly tur­nip greens. One of the richest and least expensive sources was found in yeast. In 1937, the P-P factor was identified specifically as nicotinic acid, or nia­cin, a B-complex vitamin. Adding niacin to the diet almost magically eliminates even the worst symp­toms of pellagra.

The discovery of niacin as the pellagra-preventive factor, however, did not answer all the questions about the disease. It did not explain why milk, a poor source of niacin, would prevent pellagra, nor why a diet based mostly on corn, which possesses more niacin than milk, causes it. The answer to part of the riddle lay in the discovery that the liver can convert the amino acid tryptophan, of which milk is a rich source, into niacin. The mystery of corn’s association with pellagra lies in the type of niacin it contains.

Niacin is distributed in a wide variety of foods including cereals, legumes, oilseeds, meat, tea, and coffee. Its presence in food, however, does not mean that it is always available to the body. Niacin may appear in a free form ready to be absorbed; or it may appear in a bound form called niacytin and be bio­logically unavailable, as is the case with maize. Niacytin is released only after the grain is treated with an alkali such as lime. In Mexico and Central America, where pellagra has seldom been a problem even though corn is the dietary staple, the grain is soaked in lime and heated before being baked as tortillas.

It is the high leucine content of millet jowar (.Sor­ghum vulgare) that is thought to be responsible for the appearance of pellagra in Egypt and India where this grain constitutes a large part of the diet. Niacin is found in jowar in a free form and is therefore nutritionally available, but the grain’s protein has an imbalance between leucine and the amino acid isoleucine. Like maize, jowar contains a relative ex­cess of leucine, about 12 percent, as compared with a level of below 8 percent in most other cereals. This excess brings about a conditioned niacin deficiency, one in which pyridoxine, vitamin B₆, appears to play a role.

The amount of niacin required in the diet is af­fected by the quality of protein consumed because tryptophan is a precursor of niacin. The term niacin equivalent is used because 60 milligrams of trypto­phan supply 1 milligram of niacin. An adequate diet contains 6 to 9 milligrams of niacin-equivalents per day for infants, 11 to 18 for children, and 13 to 19 for adults.

Thus the etiology of pellagra is incredibly complex. The disease may result from either a niacin defi­ciency or an amino acid imbalance. Three essential amino acids - tryptophan, leucine, and isoleucine - and two vitamins - niacin and vitamin B₆ — are in­volved. The interaction of these nutrients is not fully understood, and other nutrients as well as hormones may have a role. There is also an apparent associa­tion of pellagra with sunshine.

Regular consumption of alcohol is related to the development of pellagra, as are parasitic infections, particularly schistosomiasis. Pellagra also may be precipitated by treatment with certain drugs. Iso­niazid, used to treat tuberculosis, and 3-mercapto- purine, used to treat leukemia, can lead to a niacin deficiency. In patients with malignant carcinoid, tryptophan is diverted mainly to serotonin rather than to niacin, and pellagra may follow.

Clinical Manifestations and Pathology

Pellagra usually appears in the winter or spring and seems to disappear a few months later, only to recur the following year. Symptoms become progressively worse. In the early stages of the disease, patients feel weak, tire easily, lose their appetites, and can­not sleep. The first definite sign of the disease, how­ever, is a reddening of the skin, frequently mistaken for sunburn. In severe cases, the skin manifestation progresses rapidly and makes the disease easy to distinguish. It may appear on the feet and ankles, hands and forearms (“pellagra gloves”), or around the neck, and across the face. Lesions on the neck are called CasaVs necklace, after the Spanish physi­cian Gaspar Casal, who first identified mal de la rosa in 1735. In all cases, the skin manifestations are symmetrical and bilateral.

The first published description of pellagra, written by the French physician Franςois Thiery in 1755, was graphic. The skin, he wrote, is “a horrible crust, dry, scabby, blackish, crossed with cracks, which causes much pain to the sufferer and throws off a very foetid odor.” Although lesions usually occur on those parts of the body exposed to the sun, the geni­tals and pressure points may be affected. There is a clear demarcation between the affected and normal skin. Pellagra lesions sometimes peel, beginning from the center and spreading to the edges. In acute cases blisters occur. These may rupture, leaving weeping areas that resemble third-degree burns.

Although dermatitis is the diagnostic feature, the disease also affects the gastrointestinal tract. Pa­tients may be nauseated or suffer from excessive salivation, have a reddened tongue, or experience a burning sensation in the abdomen. These symptoms, although associated with pellagra, are usually due to deficiencies of B-complex vitamins other than nia­cin.

Particularly distressing are the neurological symp­toms. Insomnia is an early complaint, and patients are often apprehensive. Peripheral neuritis makes the movements of pellagrins uncertain. Mental aber­rations are varied. Some patients suffer only mild depression, confusion, or loss of memory. Others manifest psychotic changes severe enough for admis­sion to a mental hospital. Some are suicidal. All these symptoms are caused by biochemical changes still imperfectly understood. The amino acid composi­tion of the skin is altered, and the collagen markedly reduced. The low level of urocanic acid in the skin may be related to pellagra’s characteristic photosen­sitive rash since urocanic acid acts as an ultraviolet ray trap. There are also changes in the electrical rhythms of the brain, even if mental symptoms are not present. The majority of pellagra victims show an absence of normal alpha rhythms, but theta wave activity and high-voltage delta wave activity are found. These changes are believed to be related to an altered metabolism, in the brain, of serotonin, which is synthesized from tryptophan. Serotonin is one of the biogenic amines that modulate behavior.

History and Geography

Europe

Pellagra has always been associated with maize or corn, a grain native to America and the staple food of the American Indians. Carried to Europe as early as the third voyage of Christopher Columbus, maize was at first of interest chiefly to herbalists investi­gating the medicinal properties of plants. By the middle of the seventeenth century, however, at least one herbalist observed that the grain might have a deleterious rather than a sanguine effect if con­sumed in large quantities. An herbal of Caspar Bauhinus, published posthumously in 1658 at Basel, described how boys of the Guineas roasted and burned the grains and ate them in place of bread: “[IJf they take it a little too often [they] cannot rid themselves of the itch, since the plant produces blood that is too hot and virtually burned.”

Despite this caveat, the obvious advantages of maize ensured its spread beyond the botanical gar­dens ofEurope and into the fields. Its ease of cultiva­tion and prolific yields made it an attractive substi­tute for wheat, barley, or millet. By the end of the eighteenth century, maize was widely grown in Italy, and from there spread into what is now Yugoslavia and into France, Austria, and Hungary. The ruling Hapsburgs of Austria-Hungary actively fostered its production not only because maize provided a staple food for the peasants, but because its greater yields meant larger tithes for the royal coffers.

Pellagra was first identified by Casal, a physician at the royal court of Spain. In 1735 in the town of Oviedo in the Austrias, he first noticed a kind of lep­rosy the peasants called mal de la rosa. “Since I never saw a more disgusting indigenous disease,” he wrote, “I thought I should explain its characteristics.” There followed the description of the disease with its ex­treme weakness, sensations of burning, crusts on the skin, and melancholia. Casal noted that victims of the disease lived primarily on maize, and he empha­sized that the “rose” could be treated by adding to the diet milk, cheese, and other foods seldom seen by the poor. Thiery, then a physician at the court of Spain, read CasaFs manuscript and wrote a brief description of the disease for a Frenchjournal, published in 1755. Casal’s own work, Historia natural y medica de la principado de Austrias, was not published until 1762, 3 years after his death. In it, the section on mal de la rosa is set apart from other diseases discussed. It con­tains the volume’s only illustration and is written in Latin rather than Spanish. Within 10 years, the dis­ease was noted in Italy and given the name pellagra by Frapolli.

Accounts of pellagra in Spain are scarce after Casal’s report, but by the nineteenth century the disease was rampant in northern Italy and south­western France. Estimates were that 5 percent of the population of Lombardy was affected and that in the worst areas, the ratio was 1:5. In Milan in 1817, a visiting English physician found that about 66 percent of the inmates of a mental institution were pellagrins. The lack of reports of the disease from Spain during this period puzzled the French physi­cian Theophile Roussel; visiting Spain in the 1840s, he determined that some diseases called by various other names were indeed pellagra, and thus pub­lished a report to this effect. Although Spanish physi­cians resented his interference in their medical af­fairs, Roussel’s insistence that there was unity in endemic pellagra-like diseases was a step forward.

In retrospect, it is possible to see why pellagra spread as it did with the cultivation of maize. It was not the grain itself that was to blame for the malady, but the social and economic conditions that forced the poorest segment of the populace to eat an increas­ingly monotonous diet. In Spain, for example, the disease occurred in the region where the once power­ful guild that controlled the raising of Merino sheep had lost its influence. There were 321 different sheep taxes in 1758, and the formerly prosperous sheep industry was badly crippled. Peasants were left to fend for themselves. In Italy, a system of land tenure called mezzadria kept peasants impover­ished, half their crops going to the landowner to pay rent. In southern France, maize was not an impor­tant crop until the late eighteenth century, and its production in the environs of Paris was not encour­aged until 1829, the year the first pellagra case was reported in the country. The peasants who fell victim to the disease were primarily sheep herders. Their land was poor, and money and food were so scarce that they ate an exclusively vegetable diet. The French, however, were luckier than their neighbors. They benefited from the work of Roussel, who be­lieved so strongly that pellagra was caused by eating maize that he encouraged reforms to improve the food supply and the working and living conditions of the peasants. He wrote two books on pellagra, the second appearing in 1866. In this volume, he wrote that the problem of pellagra would be solved not by scientific discovery but through social progress. His arguments were persuasive enough for the French government to decrease maize cultivation for human food and encourage animal husbandry. By the turn of the century, pellagra had virtually disappeared from France.

Few people were willing to accept the idea that a disease as horrible as pellagra was caused by eco­nomic conditions. Many, however, were ready to asso­ciate it with maize. The proponents of this view were called Zeists, from zea mays, the botanical name of maize. They were led by an Italian physician, Gio­vanni Battista Marzari, who suggested that there were two problems with the corn diet of pellagrins. The grain was picked before it was ripe and molded in storage. More important, he believed that corn was lacking in certain nutritive elements. His follow­ers tended to accept the spoiled com theory and for years searched diligently for a toxin. Lodovico Balardini thought he had found it in copper-green molds growing on com. Cesare Lombroso of Turin, who was as much interested in criminology as medi­cine, spent a quarter of a century studying these molds. The spoiled corn theory was used to explain why pellagra broke out in Yucatan in 1882, when locusts destroyed the Indian com crop and the grain had to be imported from New York. Brought in the holds of ships as ballast, the grain spoiled en route. The poorer classes ate it anyway, and pellagra fol­lowed. When com crops failed again in the early years of the twentieth century, com was again im­ported to Yucatan. Again it arrived spoiled, and there were outbreaks of pellagra.

Not everyone was convinced that corn was respon­sible for pellagra. The Anti-Zeists thought that he­redity played a part, that bad air was responsible, or that the disease was caused by some unseen organ­ism, which they termed a vims. In the nineteenth century, however, the Zeists were for the most part triumphant, and when they were able to persuade governments to act in curtailing the consumption of corn, as they were in France, they met with a mea­sure of success.

America and the Third World

For a century and a half after pellagra was first described, the magnitude of the problem outside Eu­rope was not appreciated. Not until the 1890s, when the British epidemiologist Fleming Sandwith went to Egypt to serve on the staff of a hospital in Cairo, was anything about pellagra written in English. Sandwith found that many of his hookworm patients had pellagra, and he later discovered that they suf­fered from malaria and syphilis as well as other ailments. Sandwith noted that the disease was prin­cipally “country-bred,” and he associated it with a diet of com. He believed, however, that diseased com, not good com, was responsible. During the Boer War, when he was surrounded by poor Bantu people living on maize, he expected to find pellagra among them and he did, although the medical men of South Africa assured him that no such disease existed there.

When pellagra was identified in the southern United States, Sandwith was not surprised. Because this was an area where much corn was eaten, he had long suspected that the disease must be present. He expressed the “confident hope” that long unsolved pellagra problems would be mastered in the United States. The chief threat he saw to eventual success was that “enterprising” people in the South would diagnose everything as “doubtful pellagra.” If that happened, he thought, the whole question of pella­gra’s etiology would fall into disrepute. Both his hopes and his fears were realized.

Pellagra came to the attention of the American medical profession in the spring of 1907 with the diagnosis of an epidemic at a mental hospital in Alabama. The mortality rate was a shocking 64 per­cent. In the months that followed, hundreds and then thousands of cases were identified, and there was a frantic search for a cause and a cure. The Zeists had their advocates in America, as in Europe, but there was also much interest in looking for an insect vector. The Simulium fly appeared to be the most likely suspect. This theory, advanced by Louis Sambon of the London School of Tropical Medicine, was greeted with relief by agriculturists in the United States. Because of the discovery that ma­laria, yellow fever, and Rocky Mountain spotted fe­ver had insect vectors, pellagra might well have one, too. Some American physicians blamed foodstuffs other than corn, notably cane sugar and cottonseed oil.

While the search for a cause was underway, so was one for a cure. More than 200 remedies are recorded in the literature. Those most frequently tried were various arsenic compounds, both inorganic and or­ganic, the most popular being Salvarsan, used in the treatment of syphilis.

The U.S. Public Health Service began its work on pellagra soon after the first cases were diagnosed in Alabama, but it was not until 1914, when Joseph Goldberger was assigned to the problem, that real progress was made. In a matter of weeks, Goldberger identified the essential cause of the disease: Some­thing was missing in the diet. In a logical systematic way, he did what no one before him had done. He proved his case and found the missing element, al­though he did not specifically identify it.

Only 3 weeks after Goldberger began his work, he completely revamped the pellagra investigations of the U.S. Public Health Service and set them on a course that yielded fruitful results. His most impor­tant innovation was to introduce a new diet into selected institutions where pellagra was prevalent to see if the disease would disappear. Succeeding in that experiment, he then induced pellagra with a poor diet in a population of volunteer prisoners. To boost acceptance of the then novel idea that a dis­ease could be caused by a dietetic deficiency and to squelch his critics, Goldberger next attempted to transmit the disease to himself and several col­leagues. In several experiments over a course of 2 months in 1916, he used all the time-honored ways of experimentally transmitting a disease: blood, na­sal secretions, epidermal scales from skin lesions, urine, and feces. Neither he nor anyone else got pellagra.

While these “filth parties” were underway, Gold- berger began a study of the relationship of pellagra to economics. He noted that rural victims of the disease were sharecroppers and tenant farmers caught in a cycle of poverty tied to a one-crop agriculture. They grew little but cotton and used their meager share of profits to buy the “3 M” dietary articles which were all they could afford. Few grew much in the way of foodstuffs or kept a cow. Most were chronically in debt. In the mill villages, wages were kept notori­ously low so as to attract industry into the so-called New South arising out of the debacle of Civil War. It was in the company-owned South Carolina mill vil­lages that Goldberger demonstrated that poverty be­gets disease. Conducted over a period of 2 or 3 years, this epidemiological study conclusively proved that pellagrins were sick because they were poor. The study itself became a model in epidemiology. Victims of pellagra in the mill villages were poorer than those who escaped the disease.

In the 1920s, Goldberger turned from epidemio­logical studies to a search for the specific cause of pellagra. Working at the Hygienic Laboratory in Washington, D.C., a forerunner of the National Insti­tutes of Health, he began a systematic search for the specific element missing in the pellagrin’s diet. He was aided in this work by two fortuitous events. He got an animal model for his studies when research workers at Yale University determined that black tongue in dogs is an analogue of human pellagra, and, almost accidentally, he and his associates found one of the richest sources of the missing pellagra­preventive factor. In an effort to improve the dogs’ appetite for the monotonous pellagra-producing diet, they added a cake of commercial yeast to the daily ration. The results were magical. Within 4 days af­ter a dog with pellagra was given yeast, its condition had markedly improved.

The efficacy of yeast in preventing and treating pellagra was dramatically proved during the flood of the Mississippi River in the spring of 1927, when thousands of people were driven from their homes and forced to subsist on a diet even more restricted than usual. With Goldberger’s help and encourage­ment, the American Red Cross distributed tons of yeast to flood victims. Distribution of yeast became a standard feature of aid to people during the depres­sion of the 1930s. It was from yeast and liver ex­tracts, also found to be an effective pellagra preven­tive, that the missing dietary element was finally isolated.

Goldberger was studying liver extracts at the time of his death in 1929. That year there were probably more than 200,000 cases of pellagra in the United States, and the mortality rate was 33 percent. Ironi­cally, it was in the years of economic depression which followed that the incidence of pellagra began to de­crease in the United States as both the economy and government programs forced Southerners to grow something other than cotton. With diversification of agriculture and government programs that provided jobs, distributed surplus commodities, and encour­aged people to grow more foodstuffs and preserve them for winter use, the disease began to disappear.

After Goldberger’s work, the next scientific break­through in conquering the disease came from labora­tories at the University of Wisconsin, where in 1937 nicotinic acid, later named niacin, was found to be the pellagra-preventive factor. Conrad A. Elvehjem and his associates found that a deficiency of nicotinic acid caused black tongue in dogs. Subsequently, they learned that nicotinamide is as effective in treating black tongue as is nicotinic acid.

Numerous studies were made to transfer the re­sults of this research on dogs afflicted with black tongue to humans with pellagra. Tom Spies used nicotinic acid to treat pellagra patients with consid­erable success at a hospital in Cincinnati and later extended and expanded his work to Alabama. Com­menting on the work of Elvehjem and Spies and fellow workers, the New York Times noted that “an ailment which has baffled medicine for centuries has at last been relegated to the curable diseases and... American Medicine has to its credit a triumph com­parable with the conquest of yellow fever.”

The incredible complexity of pellagra has provided years of work for researchers. Grace A. Goldsmith and her co-workers at Tulane University proved that the amino acid tryptophan is a precursor of niacin, and she helped establish the recommended dietary allowances for that vitamin. Physicians in India have been responsible for the observation that pella­gra is associated with the consumption of millet. Coluthur Gopalan linked the high incidence of pella­gra on the Deccan Plateau to consumption of millet and to the grain’s high leucine content. Another Indian physician, P. S. Shankar, also noted the asso­ciation of millet with the disease and found that the drug isoniazid, given for treatment of tuberculosis, may precipitate pellagra.

The disappearance of pellagra from so much of the world where it was once endemic is due as much to economic and social factors as to advances in medi­cine. In the southern United States, enrichment of bread and flour with vitamins, begun in World War II, has certainly played a part in eliminating the disease, but so has burgeoning prosperity. The exam­ple of France in the late nineteenth century showed that government policy that encouraged a varied agriculture could result in important health bene­fits. Pellagra was finally brought under control in Italy by the 1930s, probably because of a rising stan­dard of living.

From the time when pellagra was first described in the eighteenth century, members of the upper classes have tended either to deny the existence of the dis­ease or to blame its appearance on the inherent moral weaknesses of its victims. In the American South, pellagra became a political and social issue. Its pres­ence bespoke a distinctiveness for the region that many Southerners did not welcome. In the late twenti­eth century, the disease appears in only isolated pock­ets in Egypt, Lesotho, and India. Its victims are poor, just as were the Spanish peasants who consulted Don Gaspar Casal in Asturias in 1735.

Elizabeth W. Etheridge

Bibliography

Barakat, M. R. 1976. Pellagra. In Nutrition in preventive medicine: The major deficiency syndromes, epide­miology and approaches to control, 126-35. Geneva.

Barrett-Connor₁ Elizabeth. 1967. The etiology of pellagra and its significance for modem medicine [Editorial], American Journal OfMedicine 42: 859-67.

Carpenter, Kenneth, ed. 1981. Pellagra, Benchmark Pa­pers in Biochemistry No. 2. Stroudsburg, Penna.

Conquest of Pellagra. 1980. Symposium presented by the American Institute of Nutrition, Anaheim, Cal., April 14. FederationProceedings 40: 1519-35.

Elvehjem, C. A., et al. 1937. Relation of nicotinic acid and nicotinic acid amide to canine black tongue. Journal OfAmerican Chemical Society 59: 1767-8.

1938. The isolation and identification of the anti-black tongue factor. Journal of Biological Chemistry 123: 137-49.

Etheridge, Elizabeth W. 1972. The butterfly caste: A social history of pellagra in the South. Westport, Conn.

Gopalan, C[oluthur], and Kamala S. Jaya Rao. 1975. Pella­gra and amino acid imbalance. Vitamins and hor­mones 33:505—28.

Narasinga Rao, B. S., and C. Gopalan. 1984. Niacin. Nutri­tion Reviews’ present knowledge in nutrition, 5th edi­tion, 318—31. Washington, D.C.

Roe, Daphne A. 1973. A plague of corn: The social history of pellagra. Ithaca, N.Y.

Schultz, Myron G. 1977. Joseph Goldberger and pellagra. American Journal of Tropical Medicine and Hygiene 26: 1088-92.

Srikantia, S. G. 1982. Endemic pellagra. In Human nutri­tion: Current issues and controversies, ed. A. Neu­berger and T. H. Jukes, 209—16. Lancaster, U.K.

1984. Pellagra. Hunter’s tropical medicine, 6th edition, ed. G. Thomas Strickland, 855—7. Philadelphia.

Terris, Milton, ed. 1964. Goldberger on pellagra. Baton Rouge, La.