Pellagra is clinically manifested by the 4 D' s: photosensitive dermatitis, diarrhea, dementia, and death. This is the only photosensitivity syndrome where death is included as a cardinal clinical feature.[1] The full tetrad of symptoms is usually not well developed in infants and children. This vitamin deficiency responds to treatment with nicotinic acid.[2] See the image below.
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Pellagra lesions on the neck. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/pellagra2.jpg).
Pellagra is observed in malnourished individuals and as a complication of isoniazid therapy; however, the diagnosis is often overlooked or delayed, occasionally with life-threatening consequences. Isoniazid-induced pellagra may occur despite pyridoxine supplementation.
Pellagra first was recognized in the United States in 1902, and it became an epidemic in the American South.[3] Poverty and corn consumption were the most frequently observed risk factors. The public became pellagraphobic, and patients were shunned and ostracized. Hungarian born Dr Joseph Goldberger of the United States Public Health Service eventually solved the problem. He was able to prevent and induce pellagra by using dietary modification.[2]
Pellagra is defined by the systemic disease resulting from niacin deficiency, and it is characterized by diarrhea, dermatitis, dementia, and death, which usually appear in this order. GI tract symptoms always precede dermatitis, or, according to Rille, "Pellagra begins in the stomach".[4]
Gasper Casal first described pellagra in 1762 in Oviedo, Asturias. Casal noted the malady among poor peasants of Asturias and termed it mal de la rose because all affected patients had the typical reddish and glossy rash on the dorsum of the hands and feet. Skin lesions on the neck are designated as the Casal necklace. Casal had observed that patients with pellagra were all poor, subsisted mainly on maize, and rarely ate fresh meat. Before Casal, the skin changes were termed Hiob disease; stigmata of Saint Francis of Assisi; or, in Italy, scorbuto alpino. François Thiery published the first description of pellagra in 1755. Francesco Frapolli called the disease vulgo pelagrain and first used the term pellagra in 1771.
In Italian vernacular, pellagra means "skin that is rough" and refers to the thickened, rough skin of persons with pellagra. In Italian, pelle means skin, and agra means sour. Pellagra remained endemic among maize-eating peasants of southern Europe for almost 2 centuries before it was recognized in the United States. In 1914, scientists suggested that pellagra was caused by a deficiency of some nutrient in the diet and that the disorder appeared to be related to black tongue (a condition analogous to pellagra) in dogs. In 1937, Conrad Elvehjem discovered that nicotinic acid cured black tongue.[5]
In the United States, pellagra was first reported in 1902. In Europe, the highest incidence was in the Mediterranean area. The first cases were reported in France in 1818, in Egypt in 1847, in England in 1866, and in Bulgaria in 1907. Over the following 2 decades, pellagra occurred in epidemic proportions in the American South. Poverty and the consumption of corn were the most frequently observed risk factors. The medical community implicated the consumption of spoiled maize as the cause of pellagra, which occurred among those who were less affluent; this suggestion caused economic repercussions for agriculturists.
Goldberger eventually solved the secret of the malady, which was a faulty diet. Goldberger was able to prevent and induce pellagra with dietary modifications, a landmark event in the annals of medicine, nutrition, and epidemiology. The reference range for serum nicotinic acid levels is 740-790 g; this level is decreased in patients with pellagra.
HIV infection induces a pellagralike state; plasma tryptophan levels are decreased in patients with HIV infection. High-dose nicotinamide treatment may successfully reverse this HIV-induced metabolic abnormality. Niacin is proposed to be a secondary preventive factor of AIDS in patients with HIV infection.[6, 7, 8]
Pellagra is the late stage of severe niacin deficiency. Niacin, or vitamin B-3, is a water-soluble vitamin. In 1926, Goldberger reported that nicotinamide was a preventive factor of pellagra.
Pellagra can be divided into primary and secondary forms. Primary pellagra results from inadequate nicotinic acid (ie, niacin) and/or tryptophan in the diet (long-term parenteral nutrition without appropriate niacin substitution; anorexia nervosa; a self-imposed restriction diet in adult atopics with sensitizations to multiple foodstuffs). Niacin is a pyridine carboxylic acid that is converted into an amide in the body.
Niacin is required for adequate cellular function and metabolism as an essential component in coenzyme I (oxidized form of nicotinamide adenine dinucleotide [NAD]) and coenzyme II (reduced form of nicotinamide adenine dinucleotide phosphate [NADP]), which either donate or accept hydrogen ions in vital oxidation-reduction reactions. These compounds are important coenzymes for glycolysis, protein and amino acid metabolism, pyruvate metabolism, pentose biosynthesis, high-energy phosphate bond generation, glycerol metabolism, and fatty acid metabolism.
Nicotinamide has an in vitro down-regulatory effect on proinflammatory cytokines interleukin (IL)–1beta, IL-6, IL-8, IL-12, and tumor necrosis factor-alpha in a dose-dependent manner. Furthermore, it induces activation of tumor necrosis factor cachectin–induced macrophages and inhibits the expression of intercellular adhesion molecule 1 and major histocompatibility complex II. . Nicotinamide is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis, mast cell histamine release, and antigen-induced lymphocyte transformation. It is able to scavenge oxygen radicals and to inhibit nitric oxide synthase mRNA induction in activated macrophages. Nicotinamide increases biosynthesis of ceramides, which, upon degradation, produce sphingosine. This inhibits protein kinase C and decreases basal cell proliferation.
This immunomodulatory and anti-inflammatory effect of nicotinamide in vitro may have great potential for the treatment of human inflammatory diseases by inhibition of neutrophil chemotaxis and secretion of inflammatory cytokines, suppression of lymphocyte transformation, and inhibition of mast cell histamine release and blockade of histamine receptors. Beneficial effects of topically applied nicotinamide in aging skin, such as improvement in barrier functions in atopic dry skin and decreased appearance of signs of facial photoaging (eg, skin texture changes and hyperpigmentation), have been noted. Nicotinic acid can be formed from dietary tryptophan. Maize contains appreciable amounts of niacin, but this niacin is present in a bound form. Treating corn used for dietary staples (eg, tortillas) with lime results in the release of bound niacin.
Because cellular functions in multiple organs and tissues are affected by niacin deficiency, the clinical expressions of pellagra are diverse. Pathologic changes in the skin include vascular dilatation, proliferation of the endothelial lining, perivascular lymphocytic infiltration, hyperkeratinization, and subsequent atrophy of the epidermis. Mucosal inflammation and atrophy involve most of the GI tract. Evidence of glossitis and atrophy of the papillae of the tongue are characteristic findings, along with gastritis and subsequent gastric mucosal atrophy. Acute inflammation of the small intestine and colon are also commonly noted. Pathologic changes in the nervous system can be found in the brain, spinal cord, and peripheral nerves. Findings include patchy demyelinization and degeneration of the affected parts of the nervous system.
Secondary pellagra occurs when adequate quantities of niacin are present in the diet, but other diseases or conditions interfere with niacin absorption and/or processing. Examples of these conditions include prolonged diarrhea; chronic alcoholism; chronic dialysis treatment; chronic colitis, particularly ulcerative colitis or regional enteritis; cirrhosis of the liver; tuberculosis of the GI tract; malignant carcinoid tumor; and Hartnup syndrome. Alcoholism can be considered a risk factor for pellagra, which can, as well, be considered an alcoholism indicator.[9] Clinical manifestations of pellagra are a less sensitive indicator than biochemical niacin deficiency in carcinoid patients with carcinoid syndrome. Occasionally, an abortive form called pellagroid (eg, erythema pellagroids, pseudopellagra) is present. Hartnup syndrome is an inborn error of tryptophan metabolism.
In addition, the use of isoniazid is known to cause the symptoms of pellagra, as does the long-term administration of 5-fluorouracil. Isoniazid biochemically competes with niacin. Pellagra was also noted as a cutaneous adverse reaction after consumption of Kombucha tea.
Pellagra can develop in atopic dermatitis patients following elimination diets.[10] It is important to consider that there is some crossover of the clinical and histological features with pellagra and necrolytic migratory erythema.
Pellagra is the late stage of severe niacin deficiency. Primary pellagra results from inadequate nicotinic acid (ie, niacin) and/or tryptophan intake in the diet.
Secondary pellagra occurs when adequate quantities of niacin are present in the diet, but other diseases or conditions interfere with its absorption and/or processing.[17, 18, 19] Such conditions include the following:
The current incidence of pellagra in the United States is unknown. Epidemics of pellagra no longer occur. Sporadic cases of pellagra can be seen among patients with long-term alcoholism, food faddists, individuals dependent on illegal drugs, and patients with malabsorption states.[11, 12, 13]
International
Although the exact incidence of pellagra in other countries is not known, pellagra occurs mainly in developing nations in which corn and corn products are the major food sources, if the corn is not specially treated. Pellagra also occurs in ethnic populations whose diets are deficient in niacin and/or tryptophan.[14, 15]
Race
No racial predilection is reported.
Sex
No sex predilection is described. The only risk factor for pellagra is dietary deprivation of niacin.
Age
Pellagra is typically a disease that occurs in adults. Pellagra may develop in adolescents and young children if they are exposed to a pellagragenic diet. Pellagra rarely occurs in infants. Historically, dermatitis associated with kwashiorkor was mistaken for infantile pellagra.[16]
If pellagra is diagnosed and treated appropriately, the prognosis for recovery is excellent. Untreated pellagra results in death from multiorgan failure. The morbidity of pellagra is related to its effects on the organ systems involved.
Dermatitis tends to be pruritic, often with a painful burning sensation during the acute phase, although patients may be asymptomatic. The skin eventually becomes hypopigmented, and some patients consider this disfiguring.
Systemic effects of the disease include malaise, apathy, weakness, and lassitude. GI tract involvement leads to a malabsorptive state and a subsequent failure to thrive.
Neurologic manifestations include anxiety, depression, delusions, hallucinations, and stupor.
Dietary history, the three identifying factors (ie, diarrhea, dermatitis, dementia), localization (see Physical Examination below), and seasonal appearance all contribute to the diagnosis.
Early symptoms of pellagra include lassitude, weakness, loss of appetite, mild digestive disturbances, and psychiatric or emotional distress (eg, anxiety, irritability, depression).
Characteristic and pathognomonic skin changes are usually preceded by prodromal symptoms, especially those of the digestive system.
The classic triad is dermatitis, diarrhea, and dementia, not invariably appearing in this order.
The diagnosis of pellagra is difficult in the absence of cutaneous findings.
Skin lesions (pellagrodermas) are painful on sites of early erythema.
Burning sensations, headache, and weakness may occur.
In the first stage, acute pellagra resembles sunburn. The skin is red, and large blebs or blisters that may develop often exfoliate, leaving large areas of denuded epithelium that may resemble severe sunburn. The changes subside, leaving a dusky, brown-red coloration. Tanning occurs more slowly than is typical in sunburn, and exacerbation occurs after reexposure to sunlight.[4, 20, 21]
The eruption usually begins as an acute dermatitis with edema and exudative alterations, changing to an erythema on the dorsa of the hands, with pruritus and burning. Vasomotor changes of cyanosis or bleaching may be well defined, with profuse sweating and a sensation of coolness. Initial bright erythema may change to cinnamon brown in color. Characteristically, the rash is symmetric.
Blisters appear several days after the onset of erythema in some patients. The blisters may coalesce into bullae and then break. In other patients, dry brown scales and blackish crusts, resulting from hemorrhage, form after 2-4 weeks.
Redness and superficial scaling appear on areas exposed to sunlight, heat, friction, or pressure.
Late cutaneous findings
In the second stage, dermatosis becomes hard, rough, cracked, blackish, and brittle. The skin may look like that of a goose, hence the term goose skin. Patients have thickened skin that is dry, scaly, and hyperkeratotic with a parchmentlike appearance and a yellowish brown hue. The skin is darkly pigmented.
When the deficiency state is far advanced, the skin becomes progressively harder, drier, more cracked, and covered with scales and blackish crusts resulting from hemorrhages. Healing usually takes place centrifugally, with the line of demarcation remaining actively inflamed after the center of the lesion has desquamated.
Blisters are present when pellagra recurs at the same site (pemphigus pellagrosus), and they contain lymphocytes, segmented leukocytes, and histiocytes. Occasionally, pustules, crusts, and deep fissures are present.
Localization
Pellagra can affect any part of the body surface, but it more frequently appears in certain areas. The usual sites are the dorsal surfaces of the hands, face, neck, arms, and feet.[22] The changes are rarely seen elsewhere.
Hands
The backs of the hands are the most common sites for the lesions (in 77-97% of cases), with accentuation of the radial border of the dorsal aspect. Lesions may extend up the arm in the glove or gauntlet form of pellagra. The epidermis of the fingers thickens, and the articular folds disappear. Painful fissures develop on the palms and digits.
Face
Dermatitis tends to follow the distribution of the trigeminal nerve, and the skin is invariably pigmented. A symmetric butterfly eruption is frequently observed; this appearance is similar to that of lupus erythematosus. A characteristic well-marginated eruption often appears on the front of the neck (ie, Casal necklace). Compared with scales elsewhere, scales on the face are thicker and larger and frequently become pustular.
The symmetry and clear line of demarcation from unaffected skin are especially striking. Lesions tend to spread from the sides to the rest of the nose; forehead; cheeks; chin; lips; and, more rarely, eyelids and ears. On the forehead, a narrow border of unaffected skin always appears between the erythema and the hair. Facial lesions never appear independent of lesions on the hands and elsewhere.
Neck
The Casal necklace extends as a fairly broad band or collar around the entire neck (cervical dermatoma with C3 and C4 innervation).
If the band is incomplete, the symmetry of the lesions is striking. The upper border extends anteriorly, somewhat below the hairline to the larynx. The lower border begins under the vertebra prominens and extends to the edge of the manubrium sterni (appendix fasciolae).
In many instances, the necklace has an anterior continuation, or broad cravat, extending from the manubrium over the sternum to the level of the nipples and ending in a point or square. On the back, the border may reach the level of the scapulae.
Affected men, women, and children have the necklace; it is always accompanied by characteristic dermatitis elsewhere.
Feet
Lesions usually do not extend proximal to the malleoli, which are included and may be covered with hyperkeratotic erythema. The heels remain free of lesions. Distally, the eruption ends at the toes or on the backs of the great toes. The front and back of the leg may be involved to form a boot. On the palms and soles, skin may be yellowish, dry, rough, and scaly. In children, the palms and soles are frequently erythematous and rough.
Other sites
The shoulders, elbows, forearms, and knees are occasionally affected. Asymmetric lesions may appear at sites of old injury or stasis.
Nails
Changes are not pathognomonic. Nails are soft, crumbly, and dull. Occasionally, transversal lines are present.
Eyes
Keratoconjunctivitis and keratomalacia may occur.
Mucosal surface of the GI tract
In one third of patients, the lips, tongue, and oral mucous membranes are involved. Highly seasoned or acidic foods can cause mucous membrane inflammation and aggravate tongue and mouth soreness. Typical changes of the tongue and mucous membranes include inflammation and edema of the tongue apex and edges. The tongue is hypertrophic, with pseudomembranous furs, erosions, and ulcers; later, the tongue becomes atrophic.
Other clinical findings include cheilosis, angular stomatitis, and thrush. Bleeding from the gingiva occurs without hemorrhages (hemorrhages occur in scurvy). The lips are inflamed, rough, achy, and shiny.
GI tract
GI tract disturbances can cause poor appetite, nausea, vomiting, epigastric discomfort, abdominal pain, and increased salivation. Diarrhea, gastritis, low levels of duodenal enzymes, and achlorhydria occur in almost 50% of patients.[21]
Atrophic changes of the gastric mucosa are demonstrated on radiographs. Glossitis causes soreness of the mouth and dysphagia. Anorexia and malabsorptive diarrhea lead to a state of malnutrition and cachexia. Diarrhea results from diffuse involvement of the mucosal surface of the GI tract. Typically, stools are watery, but occasionally, they can be bloody and mucoid.
Neuropsychiatric manifestations
In mild instances, mental disturbances may be unnoticed, and patients may be slightly depressed or apathetic.[23] Neuropsychiatric manifestations include headache, irritability, poor concentration (Leere im Kopf), anxiety, delusions, hallucinations, stupor, apathy, psychomotor unrest, photophobia, tremor, ataxia, spastic paresis, fatigue, and depression.
Fatigue and insomnia progress to encephalopathy characterized by confusion, memory loss, and psychosis. Occasionally, frank disorientation, restlessness, and severe symptoms of the central nervous system occur. Peripheral neuritis and myelitis are occasionally encountered. As the disease advances, patients become disoriented, confused, and delirious. Eventually, patients become stuporous and comatose and they die.
Pellagra encephalopathy should be suspected in patients with alcohol intake presenting with rapidly progressive dementia combined with paraparesis or tetraparesis, neuropathy, visual disturbance, and myoclonus and may also be considered as a differential diagnosis of sporadic Creutzfeldt-Jakob disease.[24]
Recurrences
Recurrent erythema usually is present on skin exposed to sunshine (ie, photosensitive eruption). Invariably, cheilitis, follicular hyperkeratosis on the face, pellagrous scrotal dermatitis, pellagrous vulvitis, porphyrinuria, funicular spinal syndrome, polyneuritis, and edema may be present. Atypical pellagra is oligosymptomatic or monosymptomatic. Abortive forms are termed pellagroids. Recurrences typically occur in the spring and summer.
Dermatitis of pellagra can be distressing and disfiguring. Denudation of the vesiculated and blistered skin lesions can potentially become infected secondarily. Severe glossitis causes dysphagia. GI tract involvement leads to a malabsorptive state. Depression, anxiety, delusions, hallucinations, and coma are the neuropsychiatric complications observed in patients with pellagra. The malnourished state associated with pellagra results in death if untreated.
The therapeutic response to niacin in a patient with the typical symptoms and signs of pellagra establishes the diagnosis.
Blood counts (anemia), findings of hypoproteinemia, higher levels of serum calcium and lower levels of serum kalium and phosphorus, liver function test results, and serum porphyrin levels can help in diagnosing pellagra.
Low serum niacin, tryptophan, NAD, and NADP levels can reflect niacin deficiency and confirm the diagnosis of pellagra.
Low urinary levels of N- methylnicotinamide and pyridone suggest niacin deficiency and support the diagnosis of pellagra. The combined excretion of N- methylnicotinamide and pyridone of less than 1.5 mg in 24 hours indicates severe niacin deficiency.
Nonspecific dermatitic changes are usually evident. Early changes include a perivascular lymphohistologic infiltrate in the upper dermis, with mild edema in the papillary dermis; dilatation of capillaries; and, later, dermal fibrosis. Epidermal changes include early subcorneal blisters; pallor of the upper epidermis; and, later, hyperkeratosis, parakeratosis, and epidermal atrophy. In recurrences in the same site, blisters (pemphigus pellagrosus) contain lymphocytes, neutrophils, and histiocytes.
Oral therapy with nicotinamide or niacin usually is effective in reversing the clinical manifestations of pellagra. Because patients are often malnourished and have other vitamin deficiencies, provisions for a high-protein diet and the administration of B-complex vitamins are needed for complete recovery.[25]
Patients with acute pellagra require bedrest during the initial phase of treatment. Patients with severe glossitis require a liquid or a soft solid diet to overcome dysphagia. Ensure that the patient has a balanced diet that is rich in protein and niacin. The topical treatment of skin lesions with topical emollients may reduce discomfort.
To prevent and/or treat pellagra, prescribe a protein-rich diet with adequate calories. The addition of meats, milk, peanuts, leafy green vegetables, whole or enriched grains, and brewer's dry yeast can enhance niacin intake. In patients with oral dysphagia secondary to glossitis, a liquid or a semisolid diet may be required. The long-term inclusion of milk, meat, and eggs in the diet ensures the dietary adequacy of the proteins essential for recovery.
The primary prevention of pellagra involves an adequate diet.
Food sources of niacin and/or tryptophan include nutritional yeast, eggs, bran, peanuts, meat, poultry, fish with red meat, cereals (especially fortified cereals), legumes, and seeds.
The recommended daily allowance of niacin for infants is 5-6 mg; for children, 9-13 mg; for adults, 13-20 mg; for pregnant women, 17 mg; and for breastfeeding women, 20 mg.
Optimal supplementation is 20-30 mg daily.
Secondary prevention is as follows:
Patients should avoid sun exposure during the active phase of the disease.
Patients should follow a convenient dietary regimen.
Close dietary follow-up after the patient's recovery helps prevent the recurrence of pellagra.
Exogenous administration cures the syndrome and, within the levels prescribed, niacin use is not associated with the uncomfortable flushing observed in other conditions (eg, hypercholesterolemia). Niacinamide (nicotinamide) is usually tolerated better than nicotinic acid, and it is the preferred agent because it does not precipitate the flushing, itching, and burning observed after the ingestion of large doses of niacin.
Vladimir Hegyi, MD, PhD, Professor, Institute of Clinical and Experimental Dermatovenereology, Slovak Republic
Disclosure: Nothing to disclose.
Coauthor(s)
Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School
Disclosure: Nothing to disclose.
Specialty Editors
David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD, Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Rille JH. Medizinische Gesellchaft Leipzig. Sitzug vom 16. November 1926. Ueber Pellegra (mit Lichtbildern). Dermatol Wochenschrift. 1927. 6:189.
Elvehjem CA, Madden RJ, Strong FM, Woolley DW. Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Am Chem Soc. 1937. 59:1767-68.
Bruno MC, Vilela MA, de Oliveira CA. Study on dermatoses and their prevalence in groups of confirmed alcoholic individuals in comparison to a non-alcoholic group of individuals. An Bras Dermatol. 2013 May-Jun. 88(3):368-75.
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