Pellagra: Signs, Symptoms, Causes, Diagnosis, Treatment, Epidemiology and History

It is a disease caused by a lack of niacin (vitamin B3). Symptoms include inflamed skin, diarrhea, dementia, and mouth sores.

Areas of the skin exposed to sunlight or friction are usually affected first. Over time, the affected skin may darken, harden, begin to 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 .

Secondary pellagra is due to a poor ability to use niacin within the diet.

This can occur as a result of alcoholism, long-term diarrhea , carcinoid syndrome, Hartnup’s disease, and a number of medications such as isoniazid.

Diagnosis is usually based on symptoms and can be assisted by urinalysis.

Treatment is with niacin or nicotinamide supplements. Improvements generally start within a couple of days. General improvements in diet are also frequently recommended.

Decreasing sun exposure through sunscreen and appropriate clothing is important while skin heals. Without treatment, death can occur. It occurs most commonly in the developing world, specifically in sub-Saharan Africa.

Signs and symptoms

The classic symptoms of pellagra are diarrhea, dermatitis, dementia (“the three D’s”), and death. This is because niacin deficiency is most noticeable in parts of the body with high rates of cell turnover, such as the skin or the gastrointestinal tract.

A more complete list of symptoms includes:

  • Sensitivity to sunlight.
  • Wide neck dermatitis is a characteristic rash, in some people, dermatitis forms around the neck, a symptom known as Casal collar.
  • Pellagra-related dermatitis usually causes a rash on the face, lips, feet, or hands.
  • Hair loss.
  • Swelling. Smooth and chunky red glossitis (inflammation of the tongue).
  • Trouble sleeping
  • Soft spot.
  • Mental confusion or aggression.
  • Ataxia (lack of coordination), limb paralysis, peripheral neuritis (nerve damage).
  • Diarrhea.
  • Dilated cardiomyopathy (enlarged and weakened heart) and eventually dementia.

J. Frostig and Tom Spies (in agreement with Cleary and Cleary) described more specific psychological symptoms of pellagra as:

  • Psychosensitive disturbances (painful impressions, annoying bright lights, intolerance to odors causing nausea and vomiting, dizziness after sudden movements).
  • Psychomotor disorders (restlessness, tension and desire to fight, greater preparation for motor action) and emotional disturbances.

Despite clinical symptoms, blood level of tryptophan or urinary metabolites such as 2-pyridone / N-methylniacinamide ratio <2 or adenine nicotinamide dinucleotide / Nicotinamide adenine dinucleotide phosphate in red blood cells could be used to diagnose pellagra.

Additional symptoms of dermatitis include:

  • Red and scaly skin.
  • Areas of discoloration, ranging from red to brown.
  • Thick, crunchy, flaky, or cracked skin.
  • Itchy, burning patches of skin.

In some cases, the neurological signs of pellagra appear early on, but are often difficult to identify. As the disease progresses, possible symptoms of dementia include:

  • Apathy.
  • Depression.
  • Confusion, irritability, or mood swings.
  • Headaches.
  • Restlessness or anxiety
  • Disorientation or delusions.

Other possible symptoms of pellagra include:

  • Sores on the lips, tongue, or gums.
  • Decreased appetite.
  • Eating and drinking problems.

The diagnosis can be confirmed after rapid improvements in symptoms in patients using high doses of niacin (250-500 mg / day) or niacin-fortified foods.


Pellagra can develop according to several mechanisms, classically as a result of niacin (vitamin B3) deficiency, resulting in a decrease in nicotinamide adenine dinucleotide (NAD).

Because nicotinamide adenine dinucleotide and its phosphorylated form of Nicotinamide adenine dinucleotide phosphate (NADP) are necessary cofactors in many body processes, the pathological impact of pellagra is extensive and leads to death if left untreated. .

The first mechanism is the simple lack of niacin in the diet. Second, it can be the result of a deficiency in tryptophan, an essential amino acid found in meat, poultry, fish, eggs, and peanuts that the body converts into niacin.

Third, it can be caused by excess leucine, as it inhibits quinolinate phosphoribosyl transferase (QPRT) and inhibits the formation of niacin or nicotinic acid for nicotinamide mononucleotide (NMN) causing pellegra-like symptoms. .

Some conditions can prevent the absorption of niacin or tryptophan from the diet and lead to pellagra. Inflammation of the jejunum or ileum can prevent the absorption of nutrients, leading to pellagra, and this in turn can be caused by Crohn’s disease.

Gastroenterostomy can also cause pellagra. Chronic alcoholism can also cause malabsorption that is combined with a diet already low in niacin and tryptophan to produce pellagra.

Hartnup disease is a genetic disorder that reduces the absorption of tryptophan and leads to pellagra.

Alterations in protein metabolism can also produce symptoms similar to pellagra.

An example is carcinoid syndrome, a disease in which neuroendocrine tumors throughout the gastrointestinal tract use tryptophan as a source of serotonin production, limiting the available tryptophan for niacin synthesis.

In normal patients, only 1 percent of the tryptophan in the diet is converted to serotonin; however, in patients with carcinoid syndrome, this value can increase to 70%.

Therefore, the carcinoid syndrome can produce niacin deficiency and clinical manifestations of pellagra.

Anti-tuberculosis medication tends to bind vitamin B6 and reduce niacin synthesis, since B6 (also known as pyridoxine) is a required cofactor in the tryptophan-niacin reaction.

Several therapeutic drugs can cause pellagra.

These include the antibiotics isoniazid, which decreases available B6 by binding to it and rendering it inactive, so it cannot be used in the synthesis of niacin and chloramphenicol; the anticancer agent fluorouracil; and the immunosuppressive mercaptopurine.

What Causes Pellagra?

There are two types of pellagra, known as primary pellagra and secondary pellagra.

Primary pellagra is caused by diets low in niacin or tryptophan. Tryptophan can be converted to niacin in the body, so not getting enough can cause niacin deficiency.

Primary pellagra is more common in developing countries that depend on corn as a staple food. Corn contains niacithin, a form of niacin that humans cannot digest and absorb unless it is properly prepared.

Secondary pellagra occurs when your body cannot absorb niacin. Things that can prevent your body from absorbing niacin include:

  • Alcoholism.
  • Eating disorders.
  • Certain medications, including anticonvulsants and immunosuppressants.
  • Gastrointestinal diseases, such as Crohn’s disease and ulcerative colitis.
  • Liver cirrhosis.
  • Tumores carcinoides.
  • Hartnup disease.

How is Pellagra diagnosed?

Pellagra can be difficult to diagnose because it causes a variety of symptoms. There is also no specific test to diagnose niacin deficiency.

Instead, your doctor will start by checking for gastrointestinal problems, skin rashes, or changes in your mental state. They can also test your urine.

In many cases, diagnosing pellagra involves seeing if your symptoms respond to niacin supplements.

Treatment for Pellagra

If left untreated, pellagra can kill in four to five years. Treatment is with nicotinamide, which has the same vitamin function as niacin and a similar chemical structure, but has less toxicity.

The frequency and amount of nicotinamide administered depends on the degree to which the condition has progressed.

Primary pellagra is treated with dietary changes and a niacin or nicotinamide supplement. It may also need to be given intravenously. Nicotinamide is another form of vitamin B-3.

With early treatment, many people make a full recovery and begin to feel better within days of starting treatment.

The improvement of the skin can take several months. However, if left untreated, primary pellagra usually causes death after four to five years.

Treatment of secondary pellagra generally focuses on treating the underlying cause. However, some cases of secondary pellagra also respond well to taking niacin or nicotinamide orally or intravenously.

While recovering from primary or secondary pellagra, it is important to keep the rashes moisturized and protected with sunscreen.


While it is much less common than it used to be, thanks to advances in food production, it is still a problem in many developing countries. It can also affect people whose bodies do not adequately absorb niacin.

Pellagra can be common in people who get most of their food energy from corn, especially in rural areas of South America where corn is a staple food. If the corn is not nixtamalized, it is a poor source of tryptophan, as well as niacin.

Nixtamalization corrects niacin deficiency, and is a common practice in Native American cultures that grow corn.

After the maize cycle, symptoms generally appear during the spring, increase in the summer due to increased sun exposure, and return the following spring.

In fact, pellagra was once endemic in the poorest southern states of the United States, such as:

Mississippi and Alabama, where its cyclical appearance in the spring after heavy winter diets led to it being known as “spring sickness” (particularly when it appeared among more vulnerable children), as well as among the prison and orphanage residents studied by Dr. Joseph Goldberger .

Pellagra is common in Africa, Indonesia, and China. In prosperous societies, the majority of patients with clinical pellagra are poor, homeless, alcohol dependent, or psychiatric patients who refuse food.

Pellagra was common among prisoners in Soviet labor camps (the Gulag).

Furthermore, pellagra, as a micronutrient deficiency disease, frequently affects refugee populations and other displaced people due to their long-term unique residential circumstances and their dependence on food aid.

Refugees generally depend on the limited sources of niacin provided to them, such as peanuts; instability in nutritional content and distribution of food aid may 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 consumption of untreated corn .

In other countries, such as the Netherlands and Denmark, even with a sufficient intake of niacin, cases have been reported.

In this case, the deficiency can occur not only due to poverty or malnutrition, but also due to alcoholism, drug interactions (psychotropic, cytostatic, tuberculostatic or analgesic), HIV, vitamin B2 and B6 deficiency or malabsorption syndromes such as Hartnup’s disease and the carcinoid.


The traditional method of corn food preparation, nixtamalization, by native New World growers who had domesticated corn, required treating the grain with lime, an alkali.

Lime treatment has been shown to make niacin nutritionally available and reduce the chance of developing pellagra.

When the cultivation of corn was adopted around the world, this method of preparation was not accepted because the benefit was not understood.

The original growers, often heavily dependent on corn, did not suffer from pellagra; it became common only when corn became a staple food eaten without traditional treatment.

Pellagra was first described for its dermatological effect in Spain in 1735 by Gaspar Casal.

He explained that the disease causes dermatitis in exposed areas of the skin, 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 entitled ‘Natural History and Medicine of the Principality of Asturias’ or Natural and Medical History of the Principality of Asturias (1762).

This led to the disease being known as “Asturian leprosy” and is recognized as the first modern pathological description of a syndrome.

It was an endemic disease in northern Italy, where it was named (in Lombard) pel agra (agra = holly or serum-like, pel = skin) by Francesco Frapolli of Milan.

With pellagra affecting more than 100,000 people in Italy in the 1880s, debates broke out about how to classify the disease (as a form of scurvy, elephantiasis, or as something new), and about its causality.

In the 19th century, Roussel started a campaign in France to restrict corn consumption and eradicated the disease in France, but it remained endemic in many rural areas of Europe.

Because outbreaks of pellagra occurred in regions where corn was a dominant food crop, the most compelling hypothesis in the late 1800s, as advocated by Cesare Lombroso, was that corn carried a toxic substance or carried a 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 corn is an important food crop, led researchers to investigate processing techniques in that region.

Pellagra was studied primarily in Europe until the late 19th century, when it became an epidemic especially in the southern United States. In the early 1900s, pellagra reached epidemic proportions in the southern United States.

Between 1906 and 1940 more than 3 million Americans were affected by pellagra with more than 100,000 deaths, yet the epidemic resolved just after dietary fortification with niacin.

Pellagra deaths in South Carolina totaled 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 likely caused by a germ or some unknown toxin in corn.

Spartanburg Pelagra 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 assignment to the United States Public Health Service (PHS) and was established primarily for research.

In 1915, Joseph Goldberger , assigned to study pellagra by the United States Surgeon General, demonstrated that it was related to diet by observing outbreaks of pellagra in orphanages and psychiatric hospitals.

Goldberger noted that children between the ages of 6 and 12 (but not older or younger children in orphanages) and patients in psychiatric 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 fresh animal feed and legume protein,” Goldberger was able to show that pellagra could be prevented.

In 1926, Goldberger established that a diet that included these foods, or a small amount of brewer’s yeast, prevented pellagra.

Goldberger experimented with 11 inmates (one was fired for prostatitis). Before the experiment, inmates ate the prison fee that was given to all inmates at Rankin Prison Farm in Mississippi.

Goldberger began feeding them a restricted diet of grits, syrup, porridge, crackers, cabbage, sweet potatoes, rice, collard greens, and sugar coffee (no milk).

Healthy white male volunteers were selected as typical skin lesions were easier to see in Caucasians and this population was considered to be the least susceptible to disease and therefore provides the strongest evidence that the disease was caused. due to a nutritional deficiency.

The subjects experienced mild, but typical gastrointestinal and cognitive symptoms, and within five months of this cereal-based diet, 6 of the 11 subjects flared into the skin lesions that are necessary for the definitive diagnosis of pellagra.

The lesions first appeared 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 pellagra diagnoses were confirmed.

In the 1920s, he connected pellagra to the rural diet with corn-based diets rather than infections, contrary to common medical ideas of the time.

Despite all his efforts, few doctors took up his ideas due to the need for social reform, especially in the land system of the time, which resulted in many preventable deaths and stereotypes.

Goldberger is remembered as the “unsung hero of American clinical epidemiology.” However, he was unable to identify a specific element whose absence caused the pellagra.

In 1937, Conrad Elvehjem , a professor of biochemistry at the University of Wisconsin-Madison, showed that the vitamin niacin cured pellagra (manifested as a black tongue) in dogs.

Later studies by Dr. Tom Spies , Marion Blankenhorn, and Clark Cooper established that niacin also cured pellagra in humans, which is why Time magazine named them its 1938 Men of the Year in holistic science.

Research carried out between 1900 and 1950 found that the number of cases of women with pellagra was consistently twice the number of cases of afflicted men.

This is believed to be due to the inhibitory effect of estrogen on the conversion of the amino acid tryptophan to niacin. Some researchers of the time gave some explanations about the difference.

Gillman and Gillman linked skeletal tissue and pellagra in their research on black South Africans. They provide some of the best evidence for the skeletal manifestations of pellagra and the bone reaction in malnutrition.

They stated that radiological studies of adult pellagrines demonstrated marked osteoporosis.

A negative mineral balance was observed in the pelaggrins, which indicated active mobilization and excretion of endogenous mineral substances, and undoubtedly affected bone turnover.

Extensive dental caries were present in more than half of the pellagra patients.

In most cases, caries was associated with “severe gingival recession, sepsis, cementum exposure, and tooth loosening.”

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 southern United States during the early years of the 20th century.

Poverty and corn consumption were the most frequently observed risk factors, but the exact cause was not known, until the pioneering work of Joseph Goldberger.

A 2017 National Office for Economic Research document explored the role of cotton production in the onset of the disease.

A prominent theory is that ‘widespread cotton production displaced local production of niacin-rich foods and led poor southern farmers and mill workers to consume Midwestern ground corn, which was relatively cheap but lacked the necessary niacin to prevent pellagra. ‘

The study provided evidence in favor of the theory: there were lower rates of pellagra 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 infestation. weevil (which happened randomly).

The whole dried corn kernel contains a nutritious germ and a fine seed coat that provides some fiber. There are two important considerations for using whole grain corn.

The germ contains oil that is exposed by crushing it, so whole cornmeal and grits quickly turn rancid at room temperature and should be refrigerated.

Whole cornmeal and grits require long cooking times, as seen in the following cooking instructions for whole grains.

Place the semolina in a pan and cover it with water. Let the grits sit for a full minute, tilt the pan, and discard and discard the rind and hulls with a fine tea strainer. Cook the semolina for 50 minutes if the semolina were soaked overnight or 90 minutes if not.

Most of the niacin in mature cereal grains is present as niacithin, which is niacin bound in a complex with hemicellulose that is nutritionally unavailable. In mature corn this can be up to 90% of the total niacin content.

The nixtamalization preparation method using the whole dried corn kernel made this niacin nutritionally available and reduced the chance of developing pellagra. The niacithin is concentrated in the aleurone and germ layers that are removed by grinding.

The milling and removal of corn in the preparation of cornmeal became feasible with the development of the Beall degerminator that was originally patented in 1901 and was used to separate sand from germ in corn processing.

However, this degermination process reduces the niacin content of the cornmeal.

Casimir Funk, who helped elucidate the role of thiamine in the etiology of beriberi, was one of the first investigators of the pellagra problem.

Funk suggested that a change in the corn milling method was responsible for the pellagra outbreak, but his article on this topic was ignored.

Pellagra developed especially among vulnerable populations in institutions such as orphanages and prisons, due to 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 nearly four decades beginning in 1906.

There were an estimated 3 million cases and 100,000 deaths due to pellagra during the epidemic.

Popular culture

George Sessions, Perry’s 1941 novel Autumn in your hand, and Jean Renoir’s 1945 film adaptation The Southerner, incorporate pellagra (“spring sickness”) as an important plot in the story of an impoverished woman. Texas farm family.

Living with pellagra

Pellagra is a serious condition caused by low levels of niacin, due to malnutrition or an absorption problem. If left untreated, it can cause death.

While primary pellagra responds well to niacin supplements, secondary pellagra can be more difficult to treat, depending on the underlying cause.